The document discusses lead identification and optimization in drug design. It describes the general drug discovery process which includes target validation, assay development, high-throughput screening, hit to lead identification, and lead optimization stages. Lead optimization is one of the most important steps and involves modifying lead compounds to improve potency, selectivity, and pharmacokinetic parameters. Structure-based and ligand-based drug design approaches are used, along with in silico tools to predict properties like toxicity and ensure drug-likeness. Key steps in structure-based design include identifying the binding site and growing fragments in an iterative process until an optimized lead is obtained.
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.
PHARMACOHORE MAPPING AND VIRTUAL SCRRENING FOR RESEARCH DEPARTMENTShikha Popali
THE PHARMACOPHORE MAPPING AND VIRTUAL SCRRENING , THESE PRESENTATION INCLUDES THE DEATIL ACCOUNT ON PHARMACOPHORE, MAPPING, ITS IDENTIFIATION FEATURES, ITS CONFORMATIONAL SEARCH, INSILICO DRUG DESIGN, VIRTUAL SCREENING, PHARMACOPHORE BASED SCREENING
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.
PHARMACOHORE MAPPING AND VIRTUAL SCRRENING FOR RESEARCH DEPARTMENTShikha Popali
THE PHARMACOPHORE MAPPING AND VIRTUAL SCRRENING , THESE PRESENTATION INCLUDES THE DEATIL ACCOUNT ON PHARMACOPHORE, MAPPING, ITS IDENTIFIATION FEATURES, ITS CONFORMATIONAL SEARCH, INSILICO DRUG DESIGN, VIRTUAL SCREENING, PHARMACOPHORE BASED SCREENING
In this slide I presented the Computer Aided Drug Design and its type :
1.Structure based Drug Design
2. Ligand based Drug Design and its Applications.
The screening of chemical libraries with traditional methods, such as high-throughput screening (HTS), is expensive and time consuming. Quantitative structure–activity relation (QSAR) modeling is an alternative method that can assist in the selection of lead molecules by using the information from
reference active and inactive compounds. This approach requires good molecular descriptors that are representative of the molecular features responsible for the relevant molecular activity.
Target identification, target validation, lead identification and lead
Optimization.
• Economics of drug discovery.
• Target Discovery and validation-Role of Genomics, Proteomics and
Bioinformatics.
• Role of Nucleic acid microarrays, Protein microarrays, Antisense
technologies, siRNAs, antisense oligonucleotides, Zinc finger proteins.
• Role of transgenic animals in target validation.
molecular docking its types and de novo drug design and application and softw...GAUTAM KHUNE
This ppt deals with all the aspects related to molecular docking ,its types(rigid ,flexible and manual) and screening based on it and also deals with de novo drug design , various softwares available for docking methodologies and applications for molecular docking in new drug design
In this slide I presented the Computer Aided Drug Design and its type :
1.Structure based Drug Design
2. Ligand based Drug Design and its Applications.
The screening of chemical libraries with traditional methods, such as high-throughput screening (HTS), is expensive and time consuming. Quantitative structure–activity relation (QSAR) modeling is an alternative method that can assist in the selection of lead molecules by using the information from
reference active and inactive compounds. This approach requires good molecular descriptors that are representative of the molecular features responsible for the relevant molecular activity.
Target identification, target validation, lead identification and lead
Optimization.
• Economics of drug discovery.
• Target Discovery and validation-Role of Genomics, Proteomics and
Bioinformatics.
• Role of Nucleic acid microarrays, Protein microarrays, Antisense
technologies, siRNAs, antisense oligonucleotides, Zinc finger proteins.
• Role of transgenic animals in target validation.
molecular docking its types and de novo drug design and application and softw...GAUTAM KHUNE
This ppt deals with all the aspects related to molecular docking ,its types(rigid ,flexible and manual) and screening based on it and also deals with de novo drug design , various softwares available for docking methodologies and applications for molecular docking in new drug design
Computer Added Drug Design is one of the latest technology of medicine world. This short slide will help you to know a little about CADD.If you want to know a vast plz go throw the reference book.
RATIONAL AND TRADITIONAL DRUG DESIGN Drug Discovery.pptxsakshinalkande
It's one of the topic of subject Principle Drug Discovery include in M pharm Pharmacology 2nd sem. It include introduction about rational and traditional drug design with types and methods. It'll be beneficial for M pharm Pharmacology students.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
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Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
2. Drug Discovery
The drug discovery process generally follows the following path that
includes a hit to lead stage:
•Target Validation (TV) → Assay Development → High-Throughput
Screening (HTS) → Hit to Lead (H2L) → Lead Optimization (LO) → Pre-
Clinical Drug Development → Clinical Drug Development
•Lead Identification
7. Lead optimization
Lead identification/optimization is the one of the most important steps in drug
development.
The chemical structure of the lead compound is used as a starting point for chemical
modifications.
These lead compounds undergo more extensive optimization in a subsequent step of
drug discovery called lead optimization(LO).
Purpose
In order to improve potency, selectivity, or pharmacokinetic parameters.
Once a molecule is identified, the next step is to check its ADMET (Adsorption,
Distribution, Metabolism, Excretion and Toxicity) properties.
If the molecule has no toxicity and no mutagenicity either, it has potential for use as
lead molecule.
Further optimization gives better quality of lead molecules. These may subsequently be
developed as drug(s)
Objective
Lead molecule should be modified to get safe and effective drug molecule which could
be achieved i.e by performing the in silico studies using some software tools.
i.e the designed drug molecule should have druglikeness and should be nontoxic and
also should not bind to the offtargets. This can be ensured using various softwares and
in silico tools.
8.
9.
10.
11.
12.
13. S.No Tool Description
1 PreADMET a web-based application for
predicting ADME data and building
drug-like library using in silico
method
2 Molinspiraton Calculation of Molecular Properties
and Drug-likeness
3 EDragon application for the calculation of
molecular descriptors
4 MODEL - Molecular Descriptor Lab Computing structural and
physichemical properties of
molecules from their 3D structures.
5 Swiss ADME Calculation of oral/intestinal
absorption and BBB permeation
6 Swiss Target Prediction of the possible targets for
the designed molecules
7 Swiss Dock Perform the molecular docking
studies and calculate the binding
affinities (ΔG)
14. Types of Drug Design
By
Dr SK ARIFA BEGUM
Avanthi Institute of Pharmaceutical Sciences
15. Drug Discovery
The drug discovery process generally follows the following path that includes a hit
to lead stage:
•Target Validation (TV)
•→ Assay Development
•→High-Throughput Screening (HTS)
• →Hit to Lead (H2L)
•→Lead Optimization (LO)
•→ Pre-Clinical Drug Development
•→ Clinical Drug Development
16. TYPES OF DRUG DESIGN
The drug is most commonly an organic small molecule that activates or inhibits
the function of a biomolecule such as a protein, which in turn results in a
therapeutic benefit to the patient.
In the most basic sense, drug design involves the design of small molecules
that are complementary in shape and charge to the biomolecular target with
which they interact and therefore will bind to it.
Typically a drug target is a key molecule involved in a particular metabolic or
signaling pathway that is specific to a disease condition or pathology or to the
infectivity or survival of a microbial pathogen.
Ligand-based drug design Also called indirect drug design which relies on
knowledge of other molecules that bind to the biological target of interest.
These other molecules may be used to derive a pharmacophore* model that
defines the minimum necessary structural characteristics a molecule must
possess in order to bind to the target.
17.
18. Structure-based drug design
Also called direct drug design which relies on knowledge of the three dimensional
structure of the biological target obtained through methods such as x-ray
crystallography or NMR spectroscopy.
If an experimental structure of a target is not available, it may be possible to create a
homology model of the target based on the experimental structure of a related
protein.
Current methods for structurebased drug design can be divided roughly into two
categories.
(1)“finding” ligands for a given receptor using database search a large number of
potential ligand molecules are screened to find those fitting the binding pocket of the
receptor. The key advantage of database searching is that it saves synthetic effort to
obtain new lead compounds.
(2) “building” ligands Ligand molecules are built up within the constraints of the
binding pocket by assembling small pieces in a stepwise manner. These pieces can be
either individual atoms or molecular fragments. The key advantage of such a method
is that novel structures, not contained in any database, can be suggested.
19.
20. The process of structure-based drug design is an iterative one (see Figure) and often
proceeds through multiple cycles before an optimized lead goes into phase I clinical
trials.
The first cycle includes the cloning, purification and structure determination of the
target protein or nucleic acid by X-ray crystallography, NMR, or homology modeling.
Using computer algorithms, compounds or fragments are positioned into a selected
region of the structure.
These compounds are scored and ranked based on their steric and electrostatic
interactions with the target site, and the best compounds are tested with biochemical
assays.
In the second cycle structure determination of the target in complex with a promising
lead from the first cycle, one with at least micromolar inhibition in vitro, reveals sites on
the compound that can be optimized to increase potency.
Additontional cycles include synthesis of the optimized lead, structure determination of
the new target:lead complex, and further optimization of the lead compound.
After several cycles of the drug design process, the optimized compounds usually
21. Overall steps involved
Link the fragments- Grow the fragments-Score the functions
Active site identification of the target biomolecule
Active site identification is the first step It analyzes the protein to find the binding
pocket, derives key interaction sites within the binding pocket, and then prepares the
necessary data for Ligand fragment link.
The basic inputs for this step are the 3D structure of the protein and a pre-docked
ligand in PDB format, as well as their atomic properties. Both ligand and protein
atoms need to be classified and their atomic properties should be defined, basically,
into four atomic types: • hydrophobic atom:
All carbons in hydrocarbon chains or in aromatic groups. • H-bond donor: Oxygen
and nitrogen atoms bonded to hydrogen atom(s). • H-bond acceptor: Oxygen and
sp2 or sp hybridized nitrogen atoms with lone electron pair(s).
• Polar atom: Oxygen and nitrogen atoms that are neither H-bond donor nor H-bond
acceptor, sulfur, phosphorus, halogen, metal, and carbon atoms bonded to hetero-
atom(s).
22. Application of Structure based drug design
•approved drug is the carbonic anhydrase inhibitor dorzolamide, which was approved in
1995.
•Imatinib, a tyrosine kinase inhibitor designed specifically for the bcr-abl fusion protein
•Design of antipsychotics
•Cimetidine , the prototypical H2-RECEPTOR ANTAGONIST FROM WHICH THE LATER
MEMBERS OF THE CLASS WERE DEVELOPED
•Selective COX-2 inhibitors- NSAIDS
•Enfuvirtide, apeptide HIV entry inhibitor
•Nonbenzodiazepines like zolpidem, and zopiclone
•Selective serotonin reuptake inhibitors, a class of anti depressants
•Zanamivir, an antiviral drug
•Isentress,HIV Integrase inhibitors
23. PHARMACOPHORE IDENTIFICATION
Computational chemists working in the area of structure-based drug design consider
both chemical and geometric properties of the interacting molecules when developing
new pharmaceutical drugs .
The underlying assumption is that drug activity, or pharmacophoric activity, is obtained
through the molecular recognition and binding of one molecule (ligand) to a pocket of
another, usually larger, molecule (receptor).
This assumption is supported by experimental results showing molecules with geometric
and chemical complementarity in their binding conformations . When the three-
dimensional structure of the receptor is known, docking methodsn exploit both the
geometric and the chemical information available.
However, the geometric structures of relatively few molecules have been obtained via
X-ray crystallography or NMR techniques.
In an effort to develop pharmaceutical drugs for receptors whose structure is unknown,
chemists start with a collection of ligands that have been experimentally discovered to
interact with the considered receptor.
By examining the chemical properties and the possible shapes of these ligands, they try
24. The features of the pharmacophore interact with features of the receptor, while the
rest of the ligand acts as a scaffold. Once a pharmacophore has been isolated, it can
be used to further improve the activity of a pharmaceutical drug.
A pharmacophore is an ensemble of steric and electronic features that is necessary to
ensure the optimal supramolecular interactions with a specific biological target and to
trigger or block ita biological response.
The pharmacophore model can be used to identify novel ligands that will bind to the
same receptor.Historically, pharmacophores were established by Lemon Kier, developed
by Paul Ehrlich.
Once the pharmacophore is identified structural modifications can be done to improve
the pharmacokinetic properties of the drug. For example the presence of the phenyl
ring , asymmetric carbon, ethylene bridge and teritiary nitrogen are found to be
minimum structural requirement for a narcotic analgesic to become active.Similarly
presence of two anionic sites and one cationic site must be present in cholinergic
agent.
Morphine, the prototype narcotic agent has a pentacyclic structure. The complexityof
the structure leads to appearance of several side effects.
25.
26. Typical pharmacophore features include
Hydrophobic centroids, aromatic rings, hydrogen bond acceptors or donors , cations and
anions.
These pharmacophore points may be located on the ligand itself
Or
May be projected points presumed to be located in the receptor.
These features need to match different chemical groups with similar properties in order
to identify novel ligands.
Ligand – receptor interactions are typically “polar positive”, “polar negative” or
“hydrophobic”.