This document provides an overview of drug design and discovery. It discusses several approaches to drug design including natural sources, chemical modification, screening, and rational drug design. Rational drug design uses computer-aided techniques like molecular modeling to design drugs that optimally interact with biological targets linked to disease. The development of new drugs is a long multi-step process taking 10-12 years and involving target identification, preclinical testing, and human clinical trials. Computational methods like quantitative structure-activity relationships (QSAR) and molecular modeling are now widely used in drug design to accelerate the process.
Pharmacophore mapping and virtual screening techniques are discussed. Pharmacophore mapping involves defining the molecular features responsible for biological activity and aligning compounds. Key steps include identifying common binding elements, generating conformations, and determining 3D relationships between pharmacophore elements. Virtual screening then uses the pharmacophore model to filter large libraries of compounds and identify potential hits through techniques like flexible 3D searching and docking. Pharmacophore-based screening is a powerful initial filter that can greatly reduce compounds requiring more computationally expensive docking.
various approaches in drug design and molecular docking.pptxpranalpatilPranal
Various approaches used in rug design and drug discovery. The document discusses:
1. The process of drug discovery from 1900s to present, including use of chemical libraries, combinatorial chemistry, bioinformatics, and genome mining.
2. Challenges in drug discovery like high costs, failures, and lack of efficacy knowledge prior to synthesis.
3. Techniques in computer-aided drug design like docking, scoring functions, and flexible ligand docking to model drug-target interactions and identify potential drug candidates.
The document discusses several key concepts in pharmacophore modeling:
1) A pharmacophore defines the important chemical features shared among active molecules, such as hydrogen bond donors/acceptors and hydrophobic regions.
2) Bioisosteres are atoms or groups with similar physical/chemical properties that produce similar biological effects.
3) 3D pharmacophores specify the spatial relationships between features as distance ranges and angles.
4) Constrained systematic searching and ensemble distance geometry are used to identify pharmacophores from a set of molecules while considering multiple conformations.
5) Clique detection identifies all possible combinations of pharmacophoric groups in molecules by finding "maximal completely connected subgraphs".
antiviral drugs medicinal chemistry by padala varaprasadVaraprasad Padala
medicinal chemistry of antiviral drugs by padala varaprasad
mainly includes structures, SAR , mechanism of action, uses and toxicity of antiviral drugs
This document discusses the process of drug discovery, focusing on finding a lead compound. It describes the key steps as: 1) Choosing a disease target, 2) Identifying a drug target within that disease, 3) Developing a bioassay to test compounds, and 4) Finding a lead compound with the desired activity against the target. It provides details on various methods for identifying lead compounds, including screening natural products, existing drugs, and synthetic compound libraries.
Combinatorial chemistry. in drug discoveryManjuJhakhar
Combinatorial chemistry is a technique that produces large numbers of similar molecules rapidly through parallel synthesis using the same reaction conditions. There are two main types: solid phase synthesis where compounds are synthesized on resin beads, and solution phase synthesis where compounds are made in solvent. Solid phase techniques have advantages like specific reactants can be bound to beads, excess reagents can be easily removed, and products are physically distinct. Mixed combinatorial synthesis uses standard routes to produce a variety of analogs in each reaction vessel without knowing the identities, allowing testing of mixtures to find lead compounds.
Combinatorial chemistry is a technique used to rapidly produce large libraries of potential drug molecules. It allows scientists to create and evaluate thousands of similar compounds in parallel. The key advantages are that it is faster and more economical than traditional drug discovery methods. Some challenges include ensuring diversity in the compound libraries and identifying the active components within mixture samples. Solid phase synthesis and parallel/mixed synthesis are common techniques used in combinatorial chemistry approaches.
Pharmacophore mapping and virtual screening techniques are discussed. Pharmacophore mapping involves defining the molecular features responsible for biological activity and aligning compounds. Key steps include identifying common binding elements, generating conformations, and determining 3D relationships between pharmacophore elements. Virtual screening then uses the pharmacophore model to filter large libraries of compounds and identify potential hits through techniques like flexible 3D searching and docking. Pharmacophore-based screening is a powerful initial filter that can greatly reduce compounds requiring more computationally expensive docking.
various approaches in drug design and molecular docking.pptxpranalpatilPranal
Various approaches used in rug design and drug discovery. The document discusses:
1. The process of drug discovery from 1900s to present, including use of chemical libraries, combinatorial chemistry, bioinformatics, and genome mining.
2. Challenges in drug discovery like high costs, failures, and lack of efficacy knowledge prior to synthesis.
3. Techniques in computer-aided drug design like docking, scoring functions, and flexible ligand docking to model drug-target interactions and identify potential drug candidates.
The document discusses several key concepts in pharmacophore modeling:
1) A pharmacophore defines the important chemical features shared among active molecules, such as hydrogen bond donors/acceptors and hydrophobic regions.
2) Bioisosteres are atoms or groups with similar physical/chemical properties that produce similar biological effects.
3) 3D pharmacophores specify the spatial relationships between features as distance ranges and angles.
4) Constrained systematic searching and ensemble distance geometry are used to identify pharmacophores from a set of molecules while considering multiple conformations.
5) Clique detection identifies all possible combinations of pharmacophoric groups in molecules by finding "maximal completely connected subgraphs".
antiviral drugs medicinal chemistry by padala varaprasadVaraprasad Padala
medicinal chemistry of antiviral drugs by padala varaprasad
mainly includes structures, SAR , mechanism of action, uses and toxicity of antiviral drugs
This document discusses the process of drug discovery, focusing on finding a lead compound. It describes the key steps as: 1) Choosing a disease target, 2) Identifying a drug target within that disease, 3) Developing a bioassay to test compounds, and 4) Finding a lead compound with the desired activity against the target. It provides details on various methods for identifying lead compounds, including screening natural products, existing drugs, and synthetic compound libraries.
Combinatorial chemistry. in drug discoveryManjuJhakhar
Combinatorial chemistry is a technique that produces large numbers of similar molecules rapidly through parallel synthesis using the same reaction conditions. There are two main types: solid phase synthesis where compounds are synthesized on resin beads, and solution phase synthesis where compounds are made in solvent. Solid phase techniques have advantages like specific reactants can be bound to beads, excess reagents can be easily removed, and products are physically distinct. Mixed combinatorial synthesis uses standard routes to produce a variety of analogs in each reaction vessel without knowing the identities, allowing testing of mixtures to find lead compounds.
Combinatorial chemistry is a technique used to rapidly produce large libraries of potential drug molecules. It allows scientists to create and evaluate thousands of similar compounds in parallel. The key advantages are that it is faster and more economical than traditional drug discovery methods. Some challenges include ensuring diversity in the compound libraries and identifying the active components within mixture samples. Solid phase synthesis and parallel/mixed synthesis are common techniques used in combinatorial chemistry approaches.
This document provides information on antiviral and antiretroviral drugs. It begins by describing viruses and their replication processes. It then discusses several important viruses and the diseases they cause. The document outlines the mechanisms of replication for DNA, RNA, and retroviruses. It proceeds to classify antiviral drugs according to their therapeutic uses and mechanisms of action. Several specific antiviral and antiretroviral drugs are described in detail, including their mechanisms of action, pharmacokinetics, and side effects. The human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) are also discussed.
Tetracyclines,Biological sources,History,Sturctures,SAR,Mechanism of action,Spectrum of activity,Important structural units and the three acidity constants in the tetracycline molucule,amphoteric nature,epimerisation, chelation with metals,toxicity and uses.
Pharmacophore modelling and docking techniques.pptxNIDHI GUPTA
Pharmacophore modelling is used to identify the essential molecular features necessary for a ligand to bind to a biological target. A pharmacophore model can explain how structurally diverse ligands can bind to a common receptor site and can be used to design or discover new ligands that bind to the same receptor. Docking techniques are also used to model molecular recognition between ligands and biological targets. Together, pharmacophore modelling and docking can provide insights into ligand-receptor interactions and guide drug design and discovery efforts.
This document discusses methods of rational drug design, including pharmacophore-based and structure-based approaches. Pharmacophore-based rational drug design identifies essential features like electrostatic interactions, hydrogen bonding, and aromatic interactions that define a receptor's active site. Structure-based rational drug design uses computational methods to model how ligands bind to proteins and predict their binding affinity and pose. The key steps are identifying the receptor's structure and function, designing drug molecules that fit the receptor, and testing candidates through synthesis and studies.
Chronopharmacology is the branch of science which deals with the pharmacological action of a drug in relation to biological rhythm.
(Chronos: time; Pharmacon: drug; Logos: study)
It is concerned with the effects of drugs upon the timing of biological events and rhythms.
It is important to enhance the therapeutic efficacy, optimization of drug effects, minimization of adverse effects by using timing medications in relation to biological rhythm.
History:
Jean-Jaques d’Ortous de Mairan: Described circardian rhythm in plants in the 18th century.
Franz Halberg : coined the term ‘Circardian’ in 20th century (about 24 hr or about a day)
Franz Halberg : Founder of Chronobiology.
Biological Rhythm:
Biological rhythm: It is the determined rhythmic biological process or function within a defined time period.
TYPES OF RHYTHM
Circadian (last for 24 hr) – Sleep wake cycle
Infradian (> 24 hr) – Menstrual cycle
Ultradian (< 24 hr) – Neuronal firing time
Biological Clock:
An internal biological clock located in mammals, in the suprachiasmatic nucleus of the hypothalamus (SCN), delivering its message of time throughout the body.
It is responsible for circadian rhythms and annual/seasonal rhythm.
The SCN uses its connections with the autonomic nervous system for spreading its time-of-day message, either by setting the sensitivity of endocrine glands (thyroid, adrenal, ovary) or by directly controlling an endocrine output of pineal gland (i.e. melatonin synthesis)
Application:
Chronotherapy found useful in
Asthma therapy, Strokes, Sleep disorders, GI tract disorders, Allergies, Oncology etc
Recent Advances:
Casein Kinase 1 (CK-1) inhibitor: Potential new drug
Reset the circadian clock enzymes.
Uses: Jet lag, sleep disorder, bipolar disorder
Animal trials completed.
Clinical trials are awaited.
This document discusses QSAR (quantitative structure-activity relationship), which is a mathematical model that relates biological activity to physicochemical properties of molecules. QSAR can be used to predict activity of new compounds. Key parameters used in QSAR include hydrophobicity (measured by partition coefficient), electronic effects (Hammett constant), and steric effects (Taft's steric factor). These parameters influence drug absorption, distribution, and interactions with receptors. QSAR models take the form of biological activity = function(parameters) to develop relationships between activity and molecular properties.
QSAR attempts to correlate biological activity to measurable physicochemical properties through mathematical equations. It relates parameters like lipophilicity (log P), electronic effects (Hammett constants), and steric effects to biological response. Various QSAR methods exist, including Hansch analysis which uses these substituent constants in its equations. More advanced techniques like CoMFA analyze fields around aligned molecules to model activity landscapes and identify favorable regions for activity. QSAR provides a framework for drug design and predicting activities of untested compounds.
This document discusses prodrug design. It defines prodrugs as pharmacologically inert derivatives that can be converted in vivo to the active drug molecule. The goals of prodrug design are to overcome undesirable drug properties related to absorption, distribution, metabolism and toxicity. Examples are given of prodrugs that increase oral absorption or provide targeted delivery to tumors. Prodrugs are evaluated based on their physicochemical properties and pharmacokinetic profile to ensure they are converted to the active drug molecule.
Chronopharmacology is the science concerned with how the pharmacological effects of drugs vary over biological times and circadian rhythms. It takes into account that many physiological functions and disease states fluctuate over 24-hour cycles. Optimizing drug dosing according to circadian rhythms can increase efficacy and safety. Examples given include dosing asthma medications in the evening to prevent nighttime attacks, dosing blood pressure medications at night to prevent heart issues in the morning, and dosing ulcer medications at bedtime to reduce nighttime acid secretion. Recent advances include developing drug delivery systems to match circadian rhythms.
Urinary tract infections are mainly caused by bacteria like E. coli and Staphylococcus. Common symptoms include burning during urination and red or pink colored urine. Quinolones are a class of antibiotics that are highly effective against many infectious diseases, including those caused by bacteria in the urinary tract. Quinolones work by inhibiting the bacterial DNA gyrase enzyme, which is responsible for compacting DNA and allowing replication. Some examples of quinolones used to treat UTIs are ciprofloxacin, norfloxacin, and ofloxacin. Other classes of antibiotics that can be used to treat UTIs include nitrofurans, sulfa drugs, and methenamine.
The document discusses various approaches used in drug design, including quantitative structure activity relationship (QSAR) analysis. QSAR uses physicochemical parameters like partition coefficient, electronic parameters, and steric parameters to develop mathematical models correlating a drug molecule's structure to its biological activity. The goal is to predict activity for new compounds and guide drug design. Parameters commonly used in QSAR include log P for hydrophobicity, Hammett constants for electronics, and Taft constants for sterics. Methods involve Hansch analysis, Free Wilson models, and other statistical techniques.
B. PHARM 6TH SEMESTER DRUG DESIGN. FACTORS, QSAR, DRUG DISCOVERY, DRUG DEVELOPMENT, VARIOUS APPROACHES FOR DRUG DESIGN, PARTITION COEFFICIENT, HAMMETS EQUATION, TAFTS STERIC PARAMETER, HANSCH ANALYSIS
Penicillins- Mechanism of action, Antimicrobial spectrum & Antibacterial resi...ANUSHA SHAJI
Penicillins are a class of beta-lactam antibiotics that were the first antibiotics used clinically in 1941. Their mechanism of action involves inhibiting the final step of bacterial cell wall synthesis by binding to and inactivating penicillin-binding proteins. This prevents cross-linking of peptidoglycan chains, leading to cell lysis as the cell wall breaks down from autolytic enzymes and osmotic pressure. Penicillin G has a narrow spectrum, being effective against gram-positive cocci like streptococci and some gram-negative cocci, but many bacteria are inherently resistant or have developed resistance via penicillinase production. Common uses include streptococcal, pneumococcal, and meningococcal infections.
This document summarizes the laboratory synthesis of triphenyl imidazole. It begins by stating the aim of synthesizing 2,4,5 triphenyl imidazole using benzil, ammonium acetate, benzaldehyde, and glacial acetic acid via the Debus-Radziszewski reaction. It then provides details on the synthesis of benzil as a starting material and the reaction mechanism. The procedure describes heating the reactants at 100°C for 3-4 hours to form an orange solution, cooling, neutralizing with ammonium hydroxide, and filtering and drying the precipitated triphenyl imidazole product.
This document discusses antimicrobial resistance and chemotherapy. It was compiled by Prof. Anwar Baig of Anjuman I Islam's Kalsekar Technical Campus School of Pharmacy. The document covers various topics related to antimicrobial drugs including definitions of antibiotics and chemotherapy. It describes mechanisms of antimicrobial resistance such as mutation, gene transfer, drug inactivation, decreased drug accumulation, and cross-resistance. Various classes of antimicrobial drugs and ways to classify them are also mentioned.
This document provides an overview of combinatorial chemistry. It discusses the history, principles, and synthetic methods of combinatorial chemistry, including solid phase and solution phase synthesis. Screening methods like high-throughput screening and virtual screening are also covered. The applications of combinatorial chemistry in drug discovery are highlighted. In conclusion, while combinatorial chemistry has limitations, its use is increasing due to available techniques for synthesis and advantages like easy purification.
SAR versus QSAR, History and development of QSAR, Types of physicochemical
parameters, experimental and theoretical approaches for the determination of
physicochemical parameters such as Partition coefficient, Hammet’s substituent
constant and Taft’s steric constant. Hansch analysis, Free Wilson analysis, 3D-QSAR
approaches like COMFA and COMSIA.
Research Avenues in Drug discovery of natural productsDevakumar Jain
This document discusses challenges facing the pharmaceutical industry and opportunities for natural products in drug discovery. The pharmaceutical industry faces losses of patent protection for many drugs, increasing costs, and litigation. Natural products are attractive alternatives as they have evolved to be bioactive and have structures not limited by human design. Advances like high-throughput screening, metabolomics, metagenomics, and metabolic engineering can help access natural product diversity and accelerate drug discovery from natural sources.
This document discusses the process of new drug development. It begins with basic research to understand disease pathways and identify potential drug targets. Promising compounds are identified through screening and optimized in preclinical testing, which evaluates safety and effectiveness in animals. If preclinical results are satisfactory, an Investigational New Drug Application is submitted to regulators to seek approval for clinical trials in humans. The drug development process is long and rigorous, aiming to bring safe and effective medications to market while meeting regulatory guidelines.
This document provides information on antiviral and antiretroviral drugs. It begins by describing viruses and their replication processes. It then discusses several important viruses and the diseases they cause. The document outlines the mechanisms of replication for DNA, RNA, and retroviruses. It proceeds to classify antiviral drugs according to their therapeutic uses and mechanisms of action. Several specific antiviral and antiretroviral drugs are described in detail, including their mechanisms of action, pharmacokinetics, and side effects. The human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) are also discussed.
Tetracyclines,Biological sources,History,Sturctures,SAR,Mechanism of action,Spectrum of activity,Important structural units and the three acidity constants in the tetracycline molucule,amphoteric nature,epimerisation, chelation with metals,toxicity and uses.
Pharmacophore modelling and docking techniques.pptxNIDHI GUPTA
Pharmacophore modelling is used to identify the essential molecular features necessary for a ligand to bind to a biological target. A pharmacophore model can explain how structurally diverse ligands can bind to a common receptor site and can be used to design or discover new ligands that bind to the same receptor. Docking techniques are also used to model molecular recognition between ligands and biological targets. Together, pharmacophore modelling and docking can provide insights into ligand-receptor interactions and guide drug design and discovery efforts.
This document discusses methods of rational drug design, including pharmacophore-based and structure-based approaches. Pharmacophore-based rational drug design identifies essential features like electrostatic interactions, hydrogen bonding, and aromatic interactions that define a receptor's active site. Structure-based rational drug design uses computational methods to model how ligands bind to proteins and predict their binding affinity and pose. The key steps are identifying the receptor's structure and function, designing drug molecules that fit the receptor, and testing candidates through synthesis and studies.
Chronopharmacology is the branch of science which deals with the pharmacological action of a drug in relation to biological rhythm.
(Chronos: time; Pharmacon: drug; Logos: study)
It is concerned with the effects of drugs upon the timing of biological events and rhythms.
It is important to enhance the therapeutic efficacy, optimization of drug effects, minimization of adverse effects by using timing medications in relation to biological rhythm.
History:
Jean-Jaques d’Ortous de Mairan: Described circardian rhythm in plants in the 18th century.
Franz Halberg : coined the term ‘Circardian’ in 20th century (about 24 hr or about a day)
Franz Halberg : Founder of Chronobiology.
Biological Rhythm:
Biological rhythm: It is the determined rhythmic biological process or function within a defined time period.
TYPES OF RHYTHM
Circadian (last for 24 hr) – Sleep wake cycle
Infradian (> 24 hr) – Menstrual cycle
Ultradian (< 24 hr) – Neuronal firing time
Biological Clock:
An internal biological clock located in mammals, in the suprachiasmatic nucleus of the hypothalamus (SCN), delivering its message of time throughout the body.
It is responsible for circadian rhythms and annual/seasonal rhythm.
The SCN uses its connections with the autonomic nervous system for spreading its time-of-day message, either by setting the sensitivity of endocrine glands (thyroid, adrenal, ovary) or by directly controlling an endocrine output of pineal gland (i.e. melatonin synthesis)
Application:
Chronotherapy found useful in
Asthma therapy, Strokes, Sleep disorders, GI tract disorders, Allergies, Oncology etc
Recent Advances:
Casein Kinase 1 (CK-1) inhibitor: Potential new drug
Reset the circadian clock enzymes.
Uses: Jet lag, sleep disorder, bipolar disorder
Animal trials completed.
Clinical trials are awaited.
This document discusses QSAR (quantitative structure-activity relationship), which is a mathematical model that relates biological activity to physicochemical properties of molecules. QSAR can be used to predict activity of new compounds. Key parameters used in QSAR include hydrophobicity (measured by partition coefficient), electronic effects (Hammett constant), and steric effects (Taft's steric factor). These parameters influence drug absorption, distribution, and interactions with receptors. QSAR models take the form of biological activity = function(parameters) to develop relationships between activity and molecular properties.
QSAR attempts to correlate biological activity to measurable physicochemical properties through mathematical equations. It relates parameters like lipophilicity (log P), electronic effects (Hammett constants), and steric effects to biological response. Various QSAR methods exist, including Hansch analysis which uses these substituent constants in its equations. More advanced techniques like CoMFA analyze fields around aligned molecules to model activity landscapes and identify favorable regions for activity. QSAR provides a framework for drug design and predicting activities of untested compounds.
This document discusses prodrug design. It defines prodrugs as pharmacologically inert derivatives that can be converted in vivo to the active drug molecule. The goals of prodrug design are to overcome undesirable drug properties related to absorption, distribution, metabolism and toxicity. Examples are given of prodrugs that increase oral absorption or provide targeted delivery to tumors. Prodrugs are evaluated based on their physicochemical properties and pharmacokinetic profile to ensure they are converted to the active drug molecule.
Chronopharmacology is the science concerned with how the pharmacological effects of drugs vary over biological times and circadian rhythms. It takes into account that many physiological functions and disease states fluctuate over 24-hour cycles. Optimizing drug dosing according to circadian rhythms can increase efficacy and safety. Examples given include dosing asthma medications in the evening to prevent nighttime attacks, dosing blood pressure medications at night to prevent heart issues in the morning, and dosing ulcer medications at bedtime to reduce nighttime acid secretion. Recent advances include developing drug delivery systems to match circadian rhythms.
Urinary tract infections are mainly caused by bacteria like E. coli and Staphylococcus. Common symptoms include burning during urination and red or pink colored urine. Quinolones are a class of antibiotics that are highly effective against many infectious diseases, including those caused by bacteria in the urinary tract. Quinolones work by inhibiting the bacterial DNA gyrase enzyme, which is responsible for compacting DNA and allowing replication. Some examples of quinolones used to treat UTIs are ciprofloxacin, norfloxacin, and ofloxacin. Other classes of antibiotics that can be used to treat UTIs include nitrofurans, sulfa drugs, and methenamine.
The document discusses various approaches used in drug design, including quantitative structure activity relationship (QSAR) analysis. QSAR uses physicochemical parameters like partition coefficient, electronic parameters, and steric parameters to develop mathematical models correlating a drug molecule's structure to its biological activity. The goal is to predict activity for new compounds and guide drug design. Parameters commonly used in QSAR include log P for hydrophobicity, Hammett constants for electronics, and Taft constants for sterics. Methods involve Hansch analysis, Free Wilson models, and other statistical techniques.
B. PHARM 6TH SEMESTER DRUG DESIGN. FACTORS, QSAR, DRUG DISCOVERY, DRUG DEVELOPMENT, VARIOUS APPROACHES FOR DRUG DESIGN, PARTITION COEFFICIENT, HAMMETS EQUATION, TAFTS STERIC PARAMETER, HANSCH ANALYSIS
Penicillins- Mechanism of action, Antimicrobial spectrum & Antibacterial resi...ANUSHA SHAJI
Penicillins are a class of beta-lactam antibiotics that were the first antibiotics used clinically in 1941. Their mechanism of action involves inhibiting the final step of bacterial cell wall synthesis by binding to and inactivating penicillin-binding proteins. This prevents cross-linking of peptidoglycan chains, leading to cell lysis as the cell wall breaks down from autolytic enzymes and osmotic pressure. Penicillin G has a narrow spectrum, being effective against gram-positive cocci like streptococci and some gram-negative cocci, but many bacteria are inherently resistant or have developed resistance via penicillinase production. Common uses include streptococcal, pneumococcal, and meningococcal infections.
This document summarizes the laboratory synthesis of triphenyl imidazole. It begins by stating the aim of synthesizing 2,4,5 triphenyl imidazole using benzil, ammonium acetate, benzaldehyde, and glacial acetic acid via the Debus-Radziszewski reaction. It then provides details on the synthesis of benzil as a starting material and the reaction mechanism. The procedure describes heating the reactants at 100°C for 3-4 hours to form an orange solution, cooling, neutralizing with ammonium hydroxide, and filtering and drying the precipitated triphenyl imidazole product.
This document discusses antimicrobial resistance and chemotherapy. It was compiled by Prof. Anwar Baig of Anjuman I Islam's Kalsekar Technical Campus School of Pharmacy. The document covers various topics related to antimicrobial drugs including definitions of antibiotics and chemotherapy. It describes mechanisms of antimicrobial resistance such as mutation, gene transfer, drug inactivation, decreased drug accumulation, and cross-resistance. Various classes of antimicrobial drugs and ways to classify them are also mentioned.
This document provides an overview of combinatorial chemistry. It discusses the history, principles, and synthetic methods of combinatorial chemistry, including solid phase and solution phase synthesis. Screening methods like high-throughput screening and virtual screening are also covered. The applications of combinatorial chemistry in drug discovery are highlighted. In conclusion, while combinatorial chemistry has limitations, its use is increasing due to available techniques for synthesis and advantages like easy purification.
SAR versus QSAR, History and development of QSAR, Types of physicochemical
parameters, experimental and theoretical approaches for the determination of
physicochemical parameters such as Partition coefficient, Hammet’s substituent
constant and Taft’s steric constant. Hansch analysis, Free Wilson analysis, 3D-QSAR
approaches like COMFA and COMSIA.
Research Avenues in Drug discovery of natural productsDevakumar Jain
This document discusses challenges facing the pharmaceutical industry and opportunities for natural products in drug discovery. The pharmaceutical industry faces losses of patent protection for many drugs, increasing costs, and litigation. Natural products are attractive alternatives as they have evolved to be bioactive and have structures not limited by human design. Advances like high-throughput screening, metabolomics, metagenomics, and metabolic engineering can help access natural product diversity and accelerate drug discovery from natural sources.
This document discusses the process of new drug development. It begins with basic research to understand disease pathways and identify potential drug targets. Promising compounds are identified through screening and optimized in preclinical testing, which evaluates safety and effectiveness in animals. If preclinical results are satisfactory, an Investigational New Drug Application is submitted to regulators to seek approval for clinical trials in humans. The drug development process is long and rigorous, aiming to bring safe and effective medications to market while meeting regulatory guidelines.
Drug design involves finding new medications by understanding how they interact with biological targets at a molecular level. The goal is to design small organic molecules that either activate or inhibit biomolecules like proteins. Effective drug design optimizes properties like binding affinity as well as bioavailability, toxicity, and side effects. The process involves identifying lead compounds, determining their structures and effects on biological activity, and using modeling to design analogs with improved target interactions and safety profiles. Overall, drug design and development is a lengthy process taking over 10 years and costing hundreds of millions to bring a new medication to market.
The document discusses the process of developing a molecule into a drug. It begins with choosing a disease and identifying a drug target. Lead compounds are found through screening existing drugs, natural products, combinatorial synthesis or computer-aided design. Lead compounds are then optimized in pre-clinical development through studies of toxicity, pharmacokinetics, and absorption, distribution, metabolism, and excretion. This involves testing in animal and computer models to improve the compound's activity and safety profile before human clinical trials.
Medicinal chemistry involves designing and synthesizing pharmaceutical agents to benefit humanity. Key aspects include synthesis, structure-activity relationships, receptor interactions, and absorption, distribution, metabolism, and excretion. The number of new drugs approved each year has declined due to higher standards and focus on complex diseases. Medicinal chemists seek to optimize lead compounds through derivatization while balancing activities, properties, and potential off-target effects to discover safe and effective drugs.
Medicinal chemistry involves designing and synthesizing pharmaceutical agents to benefit humanity. Key aspects include synthesis, structure-activity relationships, receptor interactions, and absorption/metabolism/excretion properties. Natural products have historically provided many drug leads, with plants estimated to provide over 80% of medications in traditional medicine. Medicinal chemists work to optimize drug candidates through systematic modification and evaluation to improve potency, selectivity, and safety profiles.
Drug discovery and development is and always has been the most exciting part of clinical pharmacology. It is my attempt to compile the basic concepts from various books, articles and online journals. Feel free to comment.
The document discusses various topics related to drug development including:
- Selection of therapeutic targets based on unmet medical needs and commercial potential.
- Approaches to drug discovery including traditional empirical and modern molecular methods.
- Stages of clinical development including pre-clinical and several phases of human trials.
- Major challenges in drug development like high costs, complex regulation, and individualizing treatment.
This document discusses herbs and natural products as a major source of drug discovery. It begins by explaining how natural products, including plants, animals, and minerals, have historically formed the basis of traditional medicine and modern drugs. The majority of new drugs are still generated from natural products or compounds derived from them. The document then discusses the history of using plant extracts in medicine before the 20th century and the later focus on isolating pure chemical compounds from extracts. It provides examples of important drugs discovered this way, like morphine, aspirin, antibiotics. The rest of the document outlines the process used today in natural product drug discovery, including techniques like high-throughput screening, dereplication, and lead optimization used to identify potential drug candidates from
Bioinformatic tools can be applied throughout the drug design process to reduce costs and time. High-throughput screening allows testing of millions of compounds against protein targets. Computer modeling predicts compound activity and allows virtual screening. Molecular modeling visualizes compound-protein interactions to understand mechanisms of action. In silico models predict absorption, distribution, metabolism, and excretion to evaluate drug properties without animal testing. Bioinformatics databases provide protein and compound structure information to inform drug target and lead identification. Together these tools automate and accelerate key steps in drug design and development.
This document provides information about Anthony Crasto, a Glenmark scientist based in Navi Mumbai, India. It summarizes that he runs several free websites that provide drug and pharmaceutical information which have received millions of hits on Google. These websites help track new drugs worldwide and provide free advertising to help millions. Despite facing personal challenges with his son's health issues, Crasto's vast readership from academia and industry motivates him to continue his work through these websites.
The document discusses various aspects of the drug development process including selection of therapeutic targets, approaches to drug discovery, stages of clinical development, and major challenges. Therapeutic needs are determined based on existing therapies, commercial potential, and individualized treatment. Drug discovery approaches include traditional empirical and molecular methods. Clinical development involves phases to test safety, efficacy, and dosing. Major challenges include high costs, regulatory standards, and individualizing treatment.
The document discusses various aspects of the drug development process including selection of therapeutic targets, approaches to drug discovery, stages of clinical development, and major challenges. Therapeutic needs are determined based on existing therapies, commercial potential, and individualized treatment. Drug discovery approaches include traditional empirical and molecular methods. Clinical development involves phases to test safety, efficacy, and dosing. Major challenges include high costs, regulatory standards, and individualizing treatment.
Daniel Romo is moving his research group from Texas A&M University to Baylor University in August 2015. His group conducts synthetic, biological, and biosynthetic studies of bioactive natural products with a focus on developing novel synthetic strategies and understanding the mode of action of natural products through activity-based proteomic profiling and molecular studies. Current projects include the total synthesis of oxazolomycin and gracillins and investigating the mechanisms of rameswaralide, ophiobolin, and agelastatin A.
This is the presentation for B. Pharm. IV semester students.
It includes Introduction of Medicinal Chemistry, History and Development of Medicinal Chemistry
The document provides an overview of the history and development of medicinal chemistry. It discusses how medicinal chemistry originated from the use of natural products for medicine and evolved with the isolation and synthesis of active compounds. Key developments include the first synthetic drug arsphenamine in 1910, the discovery of penicillin in the 1940s, and new drug classes like sulfonamides, beta-lactam antibiotics, corticosteroids, and anti-cancer agents over subsequent decades. Modern techniques like computer modeling and combinatorial chemistry have further advanced drug discovery and design processes.
ESA/ACT Science Coffee: Diego Blas - Gravitational wave detection with orbita...Advanced-Concepts-Team
Presentation in the Science Coffee of the Advanced Concepts Team of the European Space Agency on the 07.06.2024.
Speaker: Diego Blas (IFAE/ICREA)
Title: Gravitational wave detection with orbital motion of Moon and artificial
Abstract:
In this talk I will describe some recent ideas to find gravitational waves from supermassive black holes or of primordial origin by studying their secular effect on the orbital motion of the Moon or satellites that are laser ranged.
Describing and Interpreting an Immersive Learning Case with the Immersion Cub...Leonel Morgado
Current descriptions of immersive learning cases are often difficult or impossible to compare. This is due to a myriad of different options on what details to include, which aspects are relevant, and on the descriptive approaches employed. Also, these aspects often combine very specific details with more general guidelines or indicate intents and rationales without clarifying their implementation. In this paper we provide a method to describe immersive learning cases that is structured to enable comparisons, yet flexible enough to allow researchers and practitioners to decide which aspects to include. This method leverages a taxonomy that classifies educational aspects at three levels (uses, practices, and strategies) and then utilizes two frameworks, the Immersive Learning Brain and the Immersion Cube, to enable a structured description and interpretation of immersive learning cases. The method is then demonstrated on a published immersive learning case on training for wind turbine maintenance using virtual reality. Applying the method results in a structured artifact, the Immersive Learning Case Sheet, that tags the case with its proximal uses, practices, and strategies, and refines the free text case description to ensure that matching details are included. This contribution is thus a case description method in support of future comparative research of immersive learning cases. We then discuss how the resulting description and interpretation can be leveraged to change immersion learning cases, by enriching them (considering low-effort changes or additions) or innovating (exploring more challenging avenues of transformation). The method holds significant promise to support better-grounded research in immersive learning.
Or: Beyond linear.
Abstract: Equivariant neural networks are neural networks that incorporate symmetries. The nonlinear activation functions in these networks result in interesting nonlinear equivariant maps between simple representations, and motivate the key player of this talk: piecewise linear representation theory.
Disclaimer: No one is perfect, so please mind that there might be mistakes and typos.
dtubbenhauer@gmail.com
Corrected slides: dtubbenhauer.com/talks.html
Authoring a personal GPT for your research and practice: How we created the Q...Leonel Morgado
Thematic analysis in qualitative research is a time-consuming and systematic task, typically done using teams. Team members must ground their activities on common understandings of the major concepts underlying the thematic analysis, and define criteria for its development. However, conceptual misunderstandings, equivocations, and lack of adherence to criteria are challenges to the quality and speed of this process. Given the distributed and uncertain nature of this process, we wondered if the tasks in thematic analysis could be supported by readily available artificial intelligence chatbots. Our early efforts point to potential benefits: not just saving time in the coding process but better adherence to criteria and grounding, by increasing triangulation between humans and artificial intelligence. This tutorial will provide a description and demonstration of the process we followed, as two academic researchers, to develop a custom ChatGPT to assist with qualitative coding in the thematic data analysis process of immersive learning accounts in a survey of the academic literature: QUAL-E Immersive Learning Thematic Analysis Helper. In the hands-on time, participants will try out QUAL-E and develop their ideas for their own qualitative coding ChatGPT. Participants that have the paid ChatGPT Plus subscription can create a draft of their assistants. The organizers will provide course materials and slide deck that participants will be able to utilize to continue development of their custom GPT. The paid subscription to ChatGPT Plus is not required to participate in this workshop, just for trying out personal GPTs during it.
When I was asked to give a companion lecture in support of ‘The Philosophy of Science’ (https://shorturl.at/4pUXz) I decided not to walk through the detail of the many methodologies in order of use. Instead, I chose to employ a long standing, and ongoing, scientific development as an exemplar. And so, I chose the ever evolving story of Thermodynamics as a scientific investigation at its best.
Conducted over a period of >200 years, Thermodynamics R&D, and application, benefitted from the highest levels of professionalism, collaboration, and technical thoroughness. New layers of application, methodology, and practice were made possible by the progressive advance of technology. In turn, this has seen measurement and modelling accuracy continually improved at a micro and macro level.
Perhaps most importantly, Thermodynamics rapidly became a primary tool in the advance of applied science/engineering/technology, spanning micro-tech, to aerospace and cosmology. I can think of no better a story to illustrate the breadth of scientific methodologies and applications at their best.
EWOCS-I: The catalog of X-ray sources in Westerlund 1 from the Extended Weste...Sérgio Sacani
Context. With a mass exceeding several 104 M⊙ and a rich and dense population of massive stars, supermassive young star clusters
represent the most massive star-forming environment that is dominated by the feedback from massive stars and gravitational interactions
among stars.
Aims. In this paper we present the Extended Westerlund 1 and 2 Open Clusters Survey (EWOCS) project, which aims to investigate
the influence of the starburst environment on the formation of stars and planets, and on the evolution of both low and high mass stars.
The primary targets of this project are Westerlund 1 and 2, the closest supermassive star clusters to the Sun.
Methods. The project is based primarily on recent observations conducted with the Chandra and JWST observatories. Specifically,
the Chandra survey of Westerlund 1 consists of 36 new ACIS-I observations, nearly co-pointed, for a total exposure time of 1 Msec.
Additionally, we included 8 archival Chandra/ACIS-S observations. This paper presents the resulting catalog of X-ray sources within
and around Westerlund 1. Sources were detected by combining various existing methods, and photon extraction and source validation
were carried out using the ACIS-Extract software.
Results. The EWOCS X-ray catalog comprises 5963 validated sources out of the 9420 initially provided to ACIS-Extract, reaching a
photon flux threshold of approximately 2 × 10−8 photons cm−2
s
−1
. The X-ray sources exhibit a highly concentrated spatial distribution,
with 1075 sources located within the central 1 arcmin. We have successfully detected X-ray emissions from 126 out of the 166 known
massive stars of the cluster, and we have collected over 71 000 photons from the magnetar CXO J164710.20-455217.
Phenomics assisted breeding in crop improvementIshaGoswami9
As the population is increasing and will reach about 9 billion upto 2050. Also due to climate change, it is difficult to meet the food requirement of such a large population. Facing the challenges presented by resource shortages, climate
change, and increasing global population, crop yield and quality need to be improved in a sustainable way over the coming decades. Genetic improvement by breeding is the best way to increase crop productivity. With the rapid progression of functional
genomics, an increasing number of crop genomes have been sequenced and dozens of genes influencing key agronomic traits have been identified. However, current genome sequence information has not been adequately exploited for understanding
the complex characteristics of multiple gene, owing to a lack of crop phenotypic data. Efficient, automatic, and accurate technologies and platforms that can capture phenotypic data that can
be linked to genomics information for crop improvement at all growth stages have become as important as genotyping. Thus,
high-throughput phenotyping has become the major bottleneck restricting crop breeding. Plant phenomics has been defined as the high-throughput, accurate acquisition and analysis of multi-dimensional phenotypes
during crop growing stages at the organism level, including the cell, tissue, organ, individual plant, plot, and field levels. With the rapid development of novel sensors, imaging technology,
and analysis methods, numerous infrastructure platforms have been developed for phenotyping.
4. Profile of Today’s Pharmaceutical Business
•Time to market: 10-12 years. By contrast, a chemist develops a
new adhesive in 3 months! Why? (Biochemical, animal, human
trials; scaleup; approvals from FDA, EPA, OSHA)
5. Administrative Support Analytical Chemistry Animal Health Anti-infective Disease Bacteriology
Behavioral Sciences Biochemistry Biology Biometrics Cardiology Cardiovascular Science Clinical Research
Communication Computer Science Cytogenetics Developmental Planning DNA Sequencing Diabetology
Document Preparation Dosage Form Development Drug Absorption Drug Degradation Drug Delivery
Electrical Engineering Electron Microscopy Electrophysiology Environmental Health & Safety Employee Resources
Endocrinology Enzymology Facilities Maintenance Fermentation Finance Formulation
Gastroenterology Graphic Design Histomorphology Intestinal Permeability Law Library Science Medical Services
Mechanical Engineering Medicinal Chemistry Molecular Biology Molecular Genetics Molecular Models
Natural Products Neurobiology Neurochemistry Neurology Neurophysiology Obesity
Oncology Organic Chemistry Pathology Peptide Chemistry Pharmacokinetics Pharmacology Photochemistry
Physical Chemistry Physiology Phytochemistry Planning Powder Flow Process Development
Project Management Protein Chemistry Psychiatry Public Relations Pulmonary Physiology
Radiochemistry Radiology Robotics Spectroscopy Statistics Sterile Manufacturing Tabletting Taxonomy
Technical Information Toxicology Transdermal Drug Delivery Veterinary Science Virology X-ray Spectroscopy
Over 100
Different
Disciplines
Working Together
Pharmaceutical R&D
A Multi-Disciplinary Team
6. Medicinal chemists today are facing a
serious challenge because of the
increased cost and enormous amount of
time taken to discover a new drug, and
also because of fierce competition
amongst different drug companies
7. Drug Discovery & Development
Identify disease
Isolate protein
involved in
disease (2-5 years)
Find a drug effective
against disease protein
(2-5 years)
Preclinical testing
(1-3 years)
Formulation
Human clinical trials
(2-10 years)
Scale-up
FDA approval
(2-3 years)
Drug Design
- Molecular Modeling
- Virtual Screening
8. Technology is impacting this process
Identify disease
Isolate protein
Find drug
Preclinical testing
GENOMICS, PROTEOMICS & BIOPHARM.
HIGH THROUGHPUT SCREENING
MOLECULAR MODELING
VIRTUAL SCREENING
COMBINATORIAL CHEMISTRY
IN VITRO & IN SILICO ADME MODELS
Potentially producing many more targets
and “personalized” targets
Screening up to 100,000 compounds a
day for activity against a target protein
Using a computer to
predict activity
Rapidly producing vast numbers
of compounds
Computer graphics & models help improve activity
Tissue and computer models begin to replace animal testing
9. History of Drug Discovery….
•1909 - First rational drug design.
•Goal: safer syphilis treatment than Atoxyl.
•Paul Erhlich and Sacachiro Hata wanted to maximize toxicity to
pathogen and minimize toxicity to human (therapeutic index).
•They found Salvarsan (which was replaced by penicillin in the
1940’s)
•1960 - First successful attempt to relate chemical structure to
biological action quantitatively (QSAR = Quantitative structure-
activity relationships). Hansch and Fujita
H2N
As
HO O
O
Atoxyl
As As
HO OH
ClH.H2N NH2.HCl
Salvarsan
Na+
10. History of Drug Discovery
• Mid to late 20th century
- understand disease states, biological structures, processes,
drug transport, distribution, metabolism.
Medicinal chemists use this knowledge to modify chemical
structure to influence a drug’s activity, stability, etc.
• procaine = local anaesthetic; Procainamide = antirhythmic
H2N
O
NHCH2CH2N(C2H5)2
H2N
O
OCH2CH2N(C2H5)2
Procaine Procainamide
12. Serendipity “Chance favors the prepared mind”
1928 Fleming studied Staph, but contamination of plates with
airborne mold. Noticed bacteria were lysed in the area of mold.
A mold product inhibited the growth of bacteria: the antibiotic
penicillin
13. R-(CH2)n-N Homologs (n=2,3,4,5.....)
(A) Homolog Approach: Homologs of a lead prepared
(B) Molecular Disconnection /Simplification
O
N CH3
O
H
NCH2CH=C C
CH2OCONH2
CH2OCONH2
C
H3
C3H7
MORPHINE PENTAZOCINE MEPROBAMATE
(C) Molecular Addition
O
N-CH2-CH=CH2
O
H
NALORPHINE
(D) Isosteric Replacements
N
H2 COOH N
H2 SO2NH2
P.A.B.A. SULFANILAMIDE
Chemical Modifications
14. Chemical Modification….
•Traditional method.
• An analog of a known, active compound is synthesized with a
minor modification, that will lead to improved Biological Activity.
Advantage and Limitation: End up with something very similar
to what you start with.
15. Screening
Testing a random and large number of different molecules for
biological activity reveals leads. Innovations have led to the
automation of synthesis (combinatorial synthesis) and testing
(high-throughput screening).
Example: Prontosil is derived from a dye that exhibited
antibacterial properties.
16. Irrational, based on serendipity & Intuition
Trial & error approach
Time consuming with low through output
No de novo design, mostly “Me Too Approach”
17. Rational Drug Design - Cimetadine (Tagamet)
Starts with a validated biological target and ends up with a drug
that optimally interacts with the target and triggers the desired
biological action.
Problem: histamine triggers release of stomach acid. Want a
histamine antagonist to prevent stomach acid release by histamine
= VALIDATED BIOLOGICAL TARGET.
Histamine analogs were synthesized with systematically varied structures
(chemical modification), and SCREENED. N-guanyl-histamine showed
some antagonist properties = LEAD compound.
18. Rational Drug Design - Cimetadine (Tagamet) - continued
b. More potent and orally active,
but thiourea found to be toxic in
clinical trials
c. Replacement of the group led to
an effective and well-tolerated
product:
a. Chemical modifications were
made of the lead = LEAD
OPTIMIZATION:
d. Eventually replaced by Zantac
with an improved safety profile
19. First generation Rational
approach in Drug design
In 1970s the medicinal chemists
considered molecules as topological
entities in 2 dimension (2D) with
associated chemical properties.
QSAR concept became quite popular.
It was implemented in computers and
constituted first generation rational
approach to drug design
20. 2nd generation rational drug design
The acceptance by medicinal chemists
of molecular modeling was favored by
the fact that the QSAR was now
supplemented by 3D visualization.
The “lock and key” complementarity is
actually supported by 3D model.
Computer aided molecular design
(CAMD) is expected to contribute to
intelligent lead
21. MECHANISM BASED DRUG-DESIGN
• Most rational approach employed today.
• Disease process is understood at molecular level & targets are well
defined.
• Drug can then be designed to effectively bind these targets & disrupt
the disease process
• Very complex & intellectual approach & therefore requires detailed
knowledge & information retrieval. (CADD Holds Great Future)
“Drug –Receptor Interaction is not merely a lock-key interaction but a
dynamic & energetically favorable one”
22. Evolutionary drug designing
Ancient times: Natural products with
biological activities used as drugs.
Chemical Era: Synthetic organic
compounds
Rationalizing design process: SAR &
Computational Chemistry based Drugs
Biochemical era: To elucidate biochemical
pathways and macromolecular structures
as target as well as drug.
24. New Targets
Includes biological Space
Small molecule Space
New druggable space ?
Existing drugs (450 Targets)
targets)
~30,000 ~3,000
Total
Genome
Druggable
genes
28. Smart Drug Discovery platform
A view of Drug Discovery road map illustrating some key multidisciplinary
technologies that enable the development of (a) Breakthrough medicines from
promising candidates (b) LO & generation processes that are relative to novel
ligands.
Tomi K Sawyer, Nature Chemical Biology 2, (12) December 2006.
29. Molecular Modeling
Model construction
Molecular mechanics
Conformational searches
Molecular dynamics
QSAR/3D QSAR
Structure-based drug design
Rational drug design
NMR and X-ray
structure determination
Combinatorial chemistry
Chemical similarity
Chemical diversity
Homology modeling
Bioinformatics
Chemoinformatics
QM, MM methods
30. What is Molecular Modeling?
Molecular Graphics: Visual representation
of molecules & their properties.
Computational Chemistry: Simulation of
atomic/molecular properties of compound
through computer solvable equations.
( b’-b’0)[ V1cos] b’ (-0) [V1cos]
Statistical Modeling: D-R, QSAR/3-D QSAR Molecular data
Information Management: Organizational databases retrieval
/search & processing of properties of 1000… of compounds.
MM = Computation + Visualization + Statistical modeling
+ Molecular Data Management
32. COMPUTATIONAL TOOLS
Quantum Mechanics (QM)
Ab-initio and semi-empirical methods
Considers electronic effect & electronic
structure of the molecule
Calculates charge distribution and orbital
energies
Can simulate bond breaking and formation
Upper atom limit of about 100-120 atoms
33. COMPUTATIONAL TOOLS
Molecular Mechanics (MM)
Totally empirical technique applicable to
both small and macromolecular systems
a molecule is described as a series of
charged points (atoms) linked by springs
(bonds)
The potential energy of molecule is
described by a mathematical function called
a FORCE FIELD
34. When Newton meets Schrödinger...
ma
F
Ĥ
Sir Isaac Newton
(1642 - 1727)
Erwin Schrödinger
(1887 - 1961)
36. Mixed Quantum-Classical
in a complex environment - QM/MM
Main idea
Partitioning the system into
1. chemical active part
treated by QM methods
2. Interface region
3. large environment that is
modeled by a classical
force field
QM
interface
Classical MM
37. Mixed Quantum-Classical
in a complex environment - QM/MM
Main idea
Partitioning the system into
1. chemical active part
treated by QM methods
2. Interface region
3. large environment that is
modeled by a classical
force field
QM
interface
Classical MM
38. Receptor Structure
Unknown Known
Unknown
Generate 3D structures,
Similarity/dissimilarity
Homology modelling
HTS, Comb. Chemistry
(Build the lock, then find the key)
Active Site Search
Receptor Based DD
de NOVO design,
3D searching
(Build or find the key that fits the lock)
Ligand
Structure
Known
Indirect DD
Ligand-Based DD
Analogs Design
2D/3D QSAR &
Pharmacophore
Rational Drug Design
(Structure-based DD)
Molecular Docking
(Drug-Receptor
interaction)
Basic modeling Strategies
39. Computer Aided Drug Design Techniques
- Physicochemical Properties Calculations
- Partition Coefficient (LogP), Dissociation Constant (pKa) etc.
- Drug Design
- Ligand Based Drug Design
- QSARs
- Pharmacophore Perception
- Structure Based Drug Design
- Docking & Scoring
- de-novo drug design
- Pharmacokinetic Modeling (QSPRs)
- Absorption, Metabolism, Distribution and Toxicity etc.
- Cheminformatics
- Database Management
- Similarity / Diversity Searches
-All techniques joins together to form VIRTUAL SCREENING protocols
40. Quantitative Structure Activity
Relationships (QSAR)
QSARs are the mathematical relationships linking chemical
structures with biological activity using physicochemical or any other
derived property as an interface.
Mathematical Methods used in QSAR includes various regression
and pattern recognition techniques.
Physicochemical or any other property used for generating QSARs is
termed as Descriptors and treated as independent variable.
Biological property is treated as dependent variable.
Biological Activity = f (Physico-chemical properties)
41. QSAR and Drug Design
New compounds with
improved biological activity
Compounds + biological activity
QSAR
43. Figure: Stage-by-stage quality assessment to reduce
costly late-stage attrition.
(Ref: Nature Review-Drug Discovery vol. 2, May 2003, 369)
Virtual Hit Series, Lead Series Identification, clinical candidate selection
44. Types of QSARs
Two Dimensional QSAR
- Classical Hansh Analysis
- Two dimensional molecular properties
Three Dimensional QSAR
- Three dimensional molecular properties
- Molecular Field Analysis
- Molecular Shape Analysis
- Distance Geometry
- Receptor Surface Analysis
45. The Effect is produced by model compound and not it’s
metabolites.
The proposed conformation is the bioactive one.
The binding site is same for all modeled compounds.
The Bioactivity explain the direct interaction of molecule and
target.
Pharmacokinetics aspects, solvent effects, diffusion, transport
are not under consideration.
QSAR ASSUMPTIONS
46. 1. Selection of training set
2. Enter biological activity data
3. Generate conformations
4. Calculate descriptors
5. Selection of statistical method
6. Generate a QSAR equation
7. Validation of QSAR equation
8. Predict for Unknown
QSAR Generation Process
47. Descriptors
1. Structural descriptors
2. Electronic descriptors
3. Quantum Mech. descriptors
4. Thermodynamic descriptors
5. Shape descriptors
6. Spatial descriptors
7. Conformational descriptors
8. Receptor descriptors
Selection of Descriptors
1. What is particularly relevant to the therapeutic target?
2. What variation is relevant to the compound series?
3. What property data can be readily measured?
4. What can be readily calculated?
50. Comparative Molecular Field Analysis
Electrostatic Field Steric Field
Blue (electropositive)
Red (electronegative)
Green (favourable)
Yellow (repulsive) regions
51. COMFA studies on oxazolone derivatives
q2 = 0.688 and r2 = 0.969
Steric Electrostatic
alignment
52. COMSIA studies on imidazole derivatives
alignment
Electrostatic
Hydrophobic/
hydrophilic
steric
q2 =0.761 and r2 = 0.945
53. 3D-QSAR - RECEPTOR SURFACE MODEL
Hypothetical receptor surface model constructed from training
set molecule’s 3D shape and activity data.
The best model can be derived by optimizing various
parameters like atomic partial charges and surface fit.
Descriptors like van der Waals energy, electrostatic energy,
and total non-bonded energy can be used to derived series of
QSAR equations using G/PLS statistical method
54.
55.
56. PHARMACOPHORE APPROCH
Types of Pharmacophore Models
Distance Geometry based Qualitative Common
Feature Hypothesis.
Quantitative Predictive Pharmacophores from a
training set with known biological activities.
Pharmacophore:
The Spatial orientation of various functional groups or
features in 3D necessary to show biological activity.
57. Pharmacophore-based Drug Design
•Examine features of inactive small molecules (ligands) and the
features of active small molecules.
•Generate a hypothesis about what chemical groups on the ligand
are necessary for biological function; what chemical groups
suppress biological function.
•Generate new ligands which have the same necessary chemical
groups in the same 3D locations. (“Mimic” the active groups)
Advantage: Don’t need to know the biological target structure
59. Training Set Molecules should be
- Diverse in structure
- Contain maximum structural information.
- Most potent within series.
Features should be selected on the basis of SAR studies of
training set
Each training set molecule should be represented by a set of
low energy conformations. Conformations generation technique
ensures broad coverage of conformational space.
Align the active conformations of the training set molecules to
find the best overlay of the corresponding features.
Judge by statistical profile & visual inspection of model.
Considerations/Assumptions
60. Pharmacophore Features
HB Acceptor & HB Donor
Hydrophobic
Hydrophobic aliphatic
Hydrophobic aromatic
Positive charge/Pos. Ionizable
Negative charge/Neg. Ionizable
Ring Aromatic
Each feature consists of four parts:
1. Chemical function
2. Location and orientation in 3D space
3. Tolerance in location
4. Weight
65. Receptor-based Drug Design
•Examine the 3D structure of the biological target (an X-ray/ NMR
structure.
•Hopefully one where the target is complexed with a small molecule
ligand (Co-crystallized)
•Look for specific chemical groups that could be part of an attractive
interaction between the target protein and the ligand.
•Design a new ligands that will have sites of complementary
interactions with the biological target.
Advantage: Visualization allows
direct design of molecules
66. Docking Process
Put a compound in the approximate area where
binding occurs
Docking algorithm encodes orientation of
compound and conformations.
Optimize binding to protein
– Minimize energy
– Hydrogen bonding
– Hydrophobic interactions
Scoring
68. De Novo Drug Design
Build compounds that are complementary to a target binding site
on a protein via “random” combination of small molecular
fragments to make complete molecule with better binding profile.
69. • Can pursue both receptor and pharmacophore-based approaches
independently
• If the binding mode of the ligand and target is known,
information from each approach can be used to help the other
Ideally, identify a structural model that explains the biological
activities of the known small molecules on the basis of their
interactions with the 3D structure of the target protein.
70. Typical projects are not purely receptor or pharmacophore-based;
they use combination of information, hopefully synergistically
71. Cheminformatics - Data Management
Need to be able to store chemical structure and
biological data for millions of data points
– Computational representation of 2D structure
Need to be able to organize thousands of active
compounds into meaningful groups
– Group similar structures together and relate to activity
Need to learn as much information as possible from the
data (data mining)
– Apply statistical methods to the structures and related
information
72. Chemical Library Issues
Which R-groups to choose
Which libraries to make
– “Fill out” existing compound collection?
– Targeted to a particular protein?
– As many compounds as possible?
Computational profiling of libraries can help
– “Virtual libraries” can be assessed on computer
73. VIRTUAL SCREENING PROTOCOL
Objective - To search chemical compounds similar to active structure.
Essential components of protocol are as follows
• Substructure Hypothesis
• Pharmacophore Hypothesis
• Shape Similarity Hypothesis
• Electronic Similarity Hypothesis
- VIRTUAL SCREENING
Library of ~ 2 lac compounds was screened
• Initially 800 compounds were short listed applying above filters.
• Further 30 compounds were selected by applying diversity & similarity
analysis.
- Compounds have been in vitro screened and found various new scaffolds
74. Virtual Screening
Build a computational model of activity for a particular
target
Use model to score compounds from “virtual” or real
libraries
Use scores to decide which to make and pass through a
real screen
We may want to virtual screen
- All of a company’s in-house compounds, to see which to
screen first
- A compound collection that could be purchased
- A potential chemistry library, to see if it is worth making,
and if so which to make
76. •1970’s: no biological target structures
known, so all pharmacophore-based
approaches.
•1990’s: recombinant DNA, cloning,
etc. helped the generation of 3D
structural data of biological targets.
•Present: plenty of structural data of
biological targets, but also improved
technology to increase pharmacophore-
based projects.
77. Drug Discovery overview (LI & LO)
•Lead discovery. Identification of a compound that triggers specific
biological actions.
•Lead optimization. Properties of the lead are tested with biological
assays; new molecules are designed and synthesized to obtain the
desired properties
84. In-Silico ADMET Models
Computational methods can predict compound properties
important to ADMET
– Solubility
– Permeability
– Absorption
– Cytochrome p450 metabolism
– Toxicity
Estimates can be made for millions of compounds, helping
reduce “attrition” – the failure rate of compounds in late
stage
85. Name of the drug discovered Biol. Activity
1. Erythromycin analogs Antibacterial
2. New Sulfonamide dervs. Antibacterial
3. Rifampicin dervs. Anti-T.B.
4. Napthoquinones Antimalerials
5. Mitomycins Antileukemia
6. Pyridine –2-methanol’s Spasmolytics
7. Cyclopropalamines MAO inhibitors
8. -Carbolines MAO Inhibitors
9. Phenyl oxazolidines Radioprotectives
10.Hydantoin dervs. Anti CNS-tumors
11.Quinolones Antibacterial
Drug Design Successes (Fruits of QSAR)
86. Drug Design Successes
While we are still waiting for a drug totally designed
from scratch, many drugs have been developed with
major contributions from computational methods
N
F
O
N
HN
CO2H
Et
norfloxacin (1983)
antibiotic
first of the 6-fluoroquinolones
QSAR studies
dorzolamide [Trusopt] (1994)
glaucoma treatment
carbonic anhydrase inhibitor
SBLD and ab initio calcs
S
O2
S
SO2NH2
NH
MeO
MeO
O
N
donepezil (1996)
Alzheimer's treatment
acetylcholinesterase inhibitor
shape analysis and docking studies
N
NH
N
N
N
N
HO
Cl
Bu
losartan [Cozaar] (1995)
angiotensin II antagonist
anti-hypertensive
Modeling Angiotensin II octapeptide
H
N
NMe 2
NH
O
H
O
zolmatriptan [Zomig] 1995
5-HT1D agonist
migraine treatment
Molecular modeling
87. Drug Design Successes-2
N
N
N
H
N
OH
Ph
O
OH
N
H
O
indinavir [Crixivan] (Merck, 1996)
X-ray data from enzyme and molecular mechanics
N
H
Me
HO
O
SPh
OH
O
H
N
H
H
nelfinivir [Viracept] (Agouron, 1996)
ritonavir [Norvir] (Abbott, 1995)
peptidomimetic strategy
saquinavir [Invirase, Fortovase] (Roche, 1990)
transition state mimic of enzyme substrate
N
H
O
Ph
OH
O
H
N
H
H
H
N
CONH 2
O
N
N
S
N
Me
N
H
H
N
N
H
O
O
O
Ph
OH
Ph
O
N
S
HIV-1 protease inhibitors
88. SUMMARY
Drug Discovery is a multidisciplinary, complex,
costly and intellect intensive process.
Modern drug design techniques can make drug
discovery process more fruitful & rational.
Knowledge management and technique
specific expertise can save time & cost,
which is a paramount need of the hour.