Medicinal chemistry involves the design and synthesis of pharmaceutical agents to benefit humanity. It includes structure-activity relationships, receptor interactions, and absorption/metabolism properties of compounds. Combinatorial chemistry produces large libraries of similar molecules for screening via techniques like solid phase synthesis and parallel/mixed synthesis. Quantitative structure-activity relationship analysis uses parameters like lipophilicity, electronic effects, and steric hindrance to develop mathematical models correlating biological activity to a compound's physicochemical properties.
This is the presentation for B. Pharm. IV semester students.
It includes Introduction of Medicinal Chemistry, History and Development of Medicinal Chemistry
This is a ppt on Medicinal chemistry, just made to help out and give the students of CLASS XI studying in CBSE about what Medicinal Chemistry is >>Please do feedback in the comments part
ANTI HYPERTENSIVE AGENTS [MEDICINAL CHEMISTRY] BY P.RAVISANKAR, HYPERTENSION,...Dr. Ravi Sankar
ANTI HYPERTENSIVE AGENTS [MEDICINAL CHEMISTRY] BY P.RAVISANKAR, HYPERTENSION,TYPES,CAUSES OF HYPERTENSION, CLASSIFICATION, MECHANISM OF ACTION, SAR, ACE INHIBITORS, ARB , DIURETICS(WATER PILLS), TIPS TO STOP SILENT KILLER.
BY P. RAVISANKAR, VIGNAN PHARMACY COLLEGE, VADLAMUDI, GUNTUR,A.P, INDIA.
DEFINITION:
The ability of a chemical compound to elicit a pharmacological/ therapeutic effect is related to the influence of various physical and chemical (physicochemical) properties of the chemical substance on the bio molecule that it interacts with.
1)Physical Properties
Physical property of drug is responsible for its action 2)Chemical Properties
The drug react extracellularly according to simple chemical reactions like neutralization, chelation, oxidation etc.
Various Physico-Chemical Properties are,
Solubility Partition Coefficient
Dissociation constant Hydrogen Bonding Ionization of Drug Redox Potential Complexation Surface activity Protein binding Isosterism
1. Solubility:
• The solubility of a substance at a given temperature is defined as the concentration of the dissolved solute, which is in equillibrium with the solid solute.
• Solubility depends on the nature of solute and solvent as well as temperature , pH & pressure.
• The solubility of drug may be expressed in terms of its affinity/philicity or repulsion/phobicity for either an aqueous or organic solvent.
The atoms and molecules of all organic substances are held together by various types of bonds (e.g. hydrogen bond, dipole –dipole, ionic bond etc.)
These forces are involved in solubility because it is the solvent-solvent, solute-solute, solvent-solute interactions that governs solubility.
Methods to improve solubility of drugs
1) Structural modification (alter the structure of molecules) 2) Use of Cosolvents (Ethanol, sorbitol,PPG,PEG)
3) Employing surfactants 4) Complexation
Importance of solubility
1. Solubility concept is important to pharmacist because it govern the preparation of liquid dosage form and the drug must be in solution before it is absorbed by the body to produce the biological activity.
2. Drug must be in solution form to interact with receptors.
This is the presentation for B. Pharm. IV semester students.
It includes Introduction of Medicinal Chemistry, History and Development of Medicinal Chemistry
This is a ppt on Medicinal chemistry, just made to help out and give the students of CLASS XI studying in CBSE about what Medicinal Chemistry is >>Please do feedback in the comments part
ANTI HYPERTENSIVE AGENTS [MEDICINAL CHEMISTRY] BY P.RAVISANKAR, HYPERTENSION,...Dr. Ravi Sankar
ANTI HYPERTENSIVE AGENTS [MEDICINAL CHEMISTRY] BY P.RAVISANKAR, HYPERTENSION,TYPES,CAUSES OF HYPERTENSION, CLASSIFICATION, MECHANISM OF ACTION, SAR, ACE INHIBITORS, ARB , DIURETICS(WATER PILLS), TIPS TO STOP SILENT KILLER.
BY P. RAVISANKAR, VIGNAN PHARMACY COLLEGE, VADLAMUDI, GUNTUR,A.P, INDIA.
DEFINITION:
The ability of a chemical compound to elicit a pharmacological/ therapeutic effect is related to the influence of various physical and chemical (physicochemical) properties of the chemical substance on the bio molecule that it interacts with.
1)Physical Properties
Physical property of drug is responsible for its action 2)Chemical Properties
The drug react extracellularly according to simple chemical reactions like neutralization, chelation, oxidation etc.
Various Physico-Chemical Properties are,
Solubility Partition Coefficient
Dissociation constant Hydrogen Bonding Ionization of Drug Redox Potential Complexation Surface activity Protein binding Isosterism
1. Solubility:
• The solubility of a substance at a given temperature is defined as the concentration of the dissolved solute, which is in equillibrium with the solid solute.
• Solubility depends on the nature of solute and solvent as well as temperature , pH & pressure.
• The solubility of drug may be expressed in terms of its affinity/philicity or repulsion/phobicity for either an aqueous or organic solvent.
The atoms and molecules of all organic substances are held together by various types of bonds (e.g. hydrogen bond, dipole –dipole, ionic bond etc.)
These forces are involved in solubility because it is the solvent-solvent, solute-solute, solvent-solute interactions that governs solubility.
Methods to improve solubility of drugs
1) Structural modification (alter the structure of molecules) 2) Use of Cosolvents (Ethanol, sorbitol,PPG,PEG)
3) Employing surfactants 4) Complexation
Importance of solubility
1. Solubility concept is important to pharmacist because it govern the preparation of liquid dosage form and the drug must be in solution before it is absorbed by the body to produce the biological activity.
2. Drug must be in solution form to interact with receptors.
This powerpoint presentation will help to know about introduction of bioisosterism by Biotechnology point of view. Hope this powerpoint presentation will your reference.
In this presentation Pharmacology III Unit V covered
Following points are included;
Various Definitions:
Acute toxicity
Subacute toxicity
Chronic toxicity
Genotoxicity,
Carcinogenicity,
Teratogenicity
Mutagenicity
General principles of treatment of poisoning
Clinical symptoms and management of various poisoning conditions.
like Barbiturate poisoning, Morphinpoisoning, Organophosphoruspoisoning, Lead poisoning, mercury poisoning, Arsenin poisoning, And its specific antidote
Malignancy is most familiar as a characterization of cancer.Chemotherapy is a category of cancer treatment that uses one or more anti-cancer drugs as part of a standardized chemotherapy regimen
-a broad-spectrum antibiotics.
-It is commonly used to treat acne, infection, and other infections caused by bacteria.
-The first of these compounds was chlortetracycline followed by oxytetracycline and tetracycline.
Tetracycline is a broad-spectrum polyketide antibiotic produced by the Streptomyces genus of Actinobacteria, indicated for use against many bacterial infections. It is a protein synthesis inhibitor. It is commonly used to treat acne today, and, more recently, rosacea, and is historically important in reducing the number of deaths from cholera. Tetracycline is marketed under the brand names Sumycin, Tetracyn, and Panmycin, among others. Actisite is a thread-like fiber formulation used in dental applications. It is also used to produce several semisynthetic derivatives, which together are known as the tetracycline antibiotics. The term "tetracycline" is also used to denote the four-ring system of this compound; "tetracyclines" are related substances that contain the same four-ring system.
Unit i.Optical Isomerism as per PCI syllabus of POC-III Ganesh Mote
Unit I optical isomerism which is included in PCI syllabus of Sem IV of POC-III subject
This Unit Includes all points of Unit I such as nomenclature, R& S, d&l, D& L isomerism, Meso compounds, diastereomers, chirality, resolution of racemic mixture, enantiomers, Asymmetric synthesis,
Introduction
Mechanisms of protein drug binding
Kinetics of protein drug binding
Classes of protein drug binding.
1. Binding of drug to blood components.
(a) Plasma proteins
(b) Blood cells
2. Binding of drug to extravascular tissue protein
Determination of Protein-drug Binding
Factors affecting protein drug binding
Significance of protein/tissue binding of drug
The phenomenon of complex formation of drug with protein is called as Protein drug binding. The proteins are particularly responsible for such an interaction. A drug can interact with several tissue components.
This powerpoint presentation will help to know about introduction of bioisosterism by Biotechnology point of view. Hope this powerpoint presentation will your reference.
In this presentation Pharmacology III Unit V covered
Following points are included;
Various Definitions:
Acute toxicity
Subacute toxicity
Chronic toxicity
Genotoxicity,
Carcinogenicity,
Teratogenicity
Mutagenicity
General principles of treatment of poisoning
Clinical symptoms and management of various poisoning conditions.
like Barbiturate poisoning, Morphinpoisoning, Organophosphoruspoisoning, Lead poisoning, mercury poisoning, Arsenin poisoning, And its specific antidote
Malignancy is most familiar as a characterization of cancer.Chemotherapy is a category of cancer treatment that uses one or more anti-cancer drugs as part of a standardized chemotherapy regimen
-a broad-spectrum antibiotics.
-It is commonly used to treat acne, infection, and other infections caused by bacteria.
-The first of these compounds was chlortetracycline followed by oxytetracycline and tetracycline.
Tetracycline is a broad-spectrum polyketide antibiotic produced by the Streptomyces genus of Actinobacteria, indicated for use against many bacterial infections. It is a protein synthesis inhibitor. It is commonly used to treat acne today, and, more recently, rosacea, and is historically important in reducing the number of deaths from cholera. Tetracycline is marketed under the brand names Sumycin, Tetracyn, and Panmycin, among others. Actisite is a thread-like fiber formulation used in dental applications. It is also used to produce several semisynthetic derivatives, which together are known as the tetracycline antibiotics. The term "tetracycline" is also used to denote the four-ring system of this compound; "tetracyclines" are related substances that contain the same four-ring system.
Unit i.Optical Isomerism as per PCI syllabus of POC-III Ganesh Mote
Unit I optical isomerism which is included in PCI syllabus of Sem IV of POC-III subject
This Unit Includes all points of Unit I such as nomenclature, R& S, d&l, D& L isomerism, Meso compounds, diastereomers, chirality, resolution of racemic mixture, enantiomers, Asymmetric synthesis,
Introduction
Mechanisms of protein drug binding
Kinetics of protein drug binding
Classes of protein drug binding.
1. Binding of drug to blood components.
(a) Plasma proteins
(b) Blood cells
2. Binding of drug to extravascular tissue protein
Determination of Protein-drug Binding
Factors affecting protein drug binding
Significance of protein/tissue binding of drug
The phenomenon of complex formation of drug with protein is called as Protein drug binding. The proteins are particularly responsible for such an interaction. A drug can interact with several tissue components.
Pharmacophore identification and novel drug designBenittabenny
pharmacophore is a part of a molecular structure that is responsible for a particular biological or pharmacological interaction that it undergoes. This identification leads to the development of designing a new drug.
Combinatorial chemistry and high throughputscreeningSaikiranKulkarni
Combinatorial chemistry is a collection of techniques which allow for the synthesis of multiple compounds at the same time.
Combinatorial chemistry is one of the important new methodologies developed by researchers in the pharmaceutical industry to reduce the time and costs associated with producing effective and competitive new drugs, By accelerating the process of chemical synthesis, this method is having a profound effect on all branches of chemistry, but especially on drug discovery.
This pdf is about the Schizophrenia.
For more details visit on YouTube; @SELF-EXPLANATORY;
https://www.youtube.com/channel/UCAiarMZDNhe1A3Rnpr_WkzA/videos
Thanks...!
Multi-source connectivity as the driver of solar wind variability in the heli...Sérgio Sacani
The ambient solar wind that flls the heliosphere originates from multiple
sources in the solar corona and is highly structured. It is often described
as high-speed, relatively homogeneous, plasma streams from coronal
holes and slow-speed, highly variable, streams whose source regions are
under debate. A key goal of ESA/NASA’s Solar Orbiter mission is to identify
solar wind sources and understand what drives the complexity seen in the
heliosphere. By combining magnetic feld modelling and spectroscopic
techniques with high-resolution observations and measurements, we show
that the solar wind variability detected in situ by Solar Orbiter in March
2022 is driven by spatio-temporal changes in the magnetic connectivity to
multiple sources in the solar atmosphere. The magnetic feld footpoints
connected to the spacecraft moved from the boundaries of a coronal hole
to one active region (12961) and then across to another region (12957). This
is refected in the in situ measurements, which show the transition from fast
to highly Alfvénic then to slow solar wind that is disrupted by the arrival of
a coronal mass ejection. Our results describe solar wind variability at 0.5 au
but are applicable to near-Earth observatories.
Deep Behavioral Phenotyping in Systems Neuroscience for Functional Atlasing a...Ana Luísa Pinho
Functional Magnetic Resonance Imaging (fMRI) provides means to characterize brain activations in response to behavior. However, cognitive neuroscience has been limited to group-level effects referring to the performance of specific tasks. To obtain the functional profile of elementary cognitive mechanisms, the combination of brain responses to many tasks is required. Yet, to date, both structural atlases and parcellation-based activations do not fully account for cognitive function and still present several limitations. Further, they do not adapt overall to individual characteristics. In this talk, I will give an account of deep-behavioral phenotyping strategies, namely data-driven methods in large task-fMRI datasets, to optimize functional brain-data collection and improve inference of effects-of-interest related to mental processes. Key to this approach is the employment of fast multi-functional paradigms rich on features that can be well parametrized and, consequently, facilitate the creation of psycho-physiological constructs to be modelled with imaging data. Particular emphasis will be given to music stimuli when studying high-order cognitive mechanisms, due to their ecological nature and quality to enable complex behavior compounded by discrete entities. I will also discuss how deep-behavioral phenotyping and individualized models applied to neuroimaging data can better account for the subject-specific organization of domain-general cognitive systems in the human brain. Finally, the accumulation of functional brain signatures brings the possibility to clarify relationships among tasks and create a univocal link between brain systems and mental functions through: (1) the development of ontologies proposing an organization of cognitive processes; and (2) brain-network taxonomies describing functional specialization. To this end, tools to improve commensurability in cognitive science are necessary, such as public repositories, ontology-based platforms and automated meta-analysis tools. I will thus discuss some brain-atlasing resources currently under development, and their applicability in cognitive as well as clinical neuroscience.
Observation of Io’s Resurfacing via Plume Deposition Using Ground-based Adapt...Sérgio Sacani
Since volcanic activity was first discovered on Io from Voyager images in 1979, changes
on Io’s surface have been monitored from both spacecraft and ground-based telescopes.
Here, we present the highest spatial resolution images of Io ever obtained from a groundbased telescope. These images, acquired by the SHARK-VIS instrument on the Large
Binocular Telescope, show evidence of a major resurfacing event on Io’s trailing hemisphere. When compared to the most recent spacecraft images, the SHARK-VIS images
show that a plume deposit from a powerful eruption at Pillan Patera has covered part
of the long-lived Pele plume deposit. Although this type of resurfacing event may be common on Io, few have been detected due to the rarity of spacecraft visits and the previously low spatial resolution available from Earth-based telescopes. The SHARK-VIS instrument ushers in a new era of high resolution imaging of Io’s surface using adaptive
optics at visible wavelengths.
Seminar of U.V. Spectroscopy by SAMIR PANDASAMIR PANDA
Spectroscopy is a branch of science dealing the study of interaction of electromagnetic radiation with matter.
Ultraviolet-visible spectroscopy refers to absorption spectroscopy or reflect spectroscopy in the UV-VIS spectral region.
Ultraviolet-visible spectroscopy is an analytical method that can measure the amount of light received by the analyte.
Slide 1: Title Slide
Extrachromosomal Inheritance
Slide 2: Introduction to Extrachromosomal Inheritance
Definition: Extrachromosomal inheritance refers to the transmission of genetic material that is not found within the nucleus.
Key Components: Involves genes located in mitochondria, chloroplasts, and plasmids.
Slide 3: Mitochondrial Inheritance
Mitochondria: Organelles responsible for energy production.
Mitochondrial DNA (mtDNA): Circular DNA molecule found in mitochondria.
Inheritance Pattern: Maternally inherited, meaning it is passed from mothers to all their offspring.
Diseases: Examples include Leber’s hereditary optic neuropathy (LHON) and mitochondrial myopathy.
Slide 4: Chloroplast Inheritance
Chloroplasts: Organelles responsible for photosynthesis in plants.
Chloroplast DNA (cpDNA): Circular DNA molecule found in chloroplasts.
Inheritance Pattern: Often maternally inherited in most plants, but can vary in some species.
Examples: Variegation in plants, where leaf color patterns are determined by chloroplast DNA.
Slide 5: Plasmid Inheritance
Plasmids: Small, circular DNA molecules found in bacteria and some eukaryotes.
Features: Can carry antibiotic resistance genes and can be transferred between cells through processes like conjugation.
Significance: Important in biotechnology for gene cloning and genetic engineering.
Slide 6: Mechanisms of Extrachromosomal Inheritance
Non-Mendelian Patterns: Do not follow Mendel’s laws of inheritance.
Cytoplasmic Segregation: During cell division, organelles like mitochondria and chloroplasts are randomly distributed to daughter cells.
Heteroplasmy: Presence of more than one type of organellar genome within a cell, leading to variation in expression.
Slide 7: Examples of Extrachromosomal Inheritance
Four O’clock Plant (Mirabilis jalapa): Shows variegated leaves due to different cpDNA in leaf cells.
Petite Mutants in Yeast: Result from mutations in mitochondrial DNA affecting respiration.
Slide 8: Importance of Extrachromosomal Inheritance
Evolution: Provides insight into the evolution of eukaryotic cells.
Medicine: Understanding mitochondrial inheritance helps in diagnosing and treating mitochondrial diseases.
Agriculture: Chloroplast inheritance can be used in plant breeding and genetic modification.
Slide 9: Recent Research and Advances
Gene Editing: Techniques like CRISPR-Cas9 are being used to edit mitochondrial and chloroplast DNA.
Therapies: Development of mitochondrial replacement therapy (MRT) for preventing mitochondrial diseases.
Slide 10: Conclusion
Summary: Extrachromosomal inheritance involves the transmission of genetic material outside the nucleus and plays a crucial role in genetics, medicine, and biotechnology.
Future Directions: Continued research and technological advancements hold promise for new treatments and applications.
Slide 11: Questions and Discussion
Invite Audience: Open the floor for any questions or further discussion on the topic.
Cancer cell metabolism: special Reference to Lactate PathwayAADYARAJPANDEY1
Normal Cell Metabolism:
Cellular respiration describes the series of steps that cells use to break down sugar and other chemicals to get the energy we need to function.
Energy is stored in the bonds of glucose and when glucose is broken down, much of that energy is released.
Cell utilize energy in the form of ATP.
The first step of respiration is called glycolysis. In a series of steps, glycolysis breaks glucose into two smaller molecules - a chemical called pyruvate. A small amount of ATP is formed during this process.
Most healthy cells continue the breakdown in a second process, called the Kreb's cycle. The Kreb's cycle allows cells to “burn” the pyruvates made in glycolysis to get more ATP.
The last step in the breakdown of glucose is called oxidative phosphorylation (Ox-Phos).
It takes place in specialized cell structures called mitochondria. This process produces a large amount of ATP. Importantly, cells need oxygen to complete oxidative phosphorylation.
If a cell completes only glycolysis, only 2 molecules of ATP are made per glucose. However, if the cell completes the entire respiration process (glycolysis - Kreb's - oxidative phosphorylation), about 36 molecules of ATP are created, giving it much more energy to use.
IN CANCER CELL:
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
introduction to WARBERG PHENOMENA:
WARBURG EFFECT Usually, cancer cells are highly glycolytic (glucose addiction) and take up more glucose than do normal cells from outside.
Otto Heinrich Warburg (; 8 October 1883 – 1 August 1970) In 1931 was awarded the Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme.
WARNBURG EFFECT : cancer cells under aerobic (well-oxygenated) conditions to metabolize glucose to lactate (aerobic glycolysis) is known as the Warburg effect. Warburg made the observation that tumor slices consume glucose and secrete lactate at a higher rate than normal tissues.
Comparing Evolved Extractive Text Summary Scores of Bidirectional Encoder Rep...University of Maribor
Slides from:
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Track: Artificial Intelligence
https://www.etran.rs/2024/en/home-english/
1. Over view on
MEDICINAL CHEMISTRY
COMBITORIAL CHEMISTRY
QSAR
BY
A.Padma M.Pharm
Assistant professor
Sankar reddy institute of pharmaceutical sciences,
Bestavaripeta, prakasm(dist).
2. What is medicinal chemistry ?
In medicinal chemistry, the chemist attempts to design and synthesize
a medicine or a pharmaceutical agent which will benefit humanity.
Such a compound could also be called a 'drug‘. Latin ars medicina,
meaning the art of healing
It involves:
• Synthesis
• Structure-Activity Relationships (SAR)
• Receptor interactions • Absorption, distribution, metabolism, and
excretion (ADME)
3. According to IUPAC:
Medicinal chemistry it concerns the discovery, the development, identification and
interpretation of mode of action of biological active compounds at the molecular level.
Medicinal chemistry covers the three stages
Discovery step: Involving choice of therapeutic target (receptor, enzyme &
target group, cellularorinvivomodel) & identification or discovery and
production of new active substances interactingwithselectedtargets. Such
compounds called LEADCOMPOUND.
An optimization step: Which deals with improvement of lead compound.
•The optimization process takes primarily into account the increase in
potency, selectivity and toxicity
Development stage: Whose purpose is continuation of improvement of
pharmacokinetic properties.
4. History of Medicinal chemistry
2000 BC Materia Medica 250 vegetables drug And 120 mineral drugs
1500 BC Egyptian papyrus ebers 700 drugs originated from
animal/plants/minerals
Emperor Frederick II issued the Magna Carta of pharmacy in 1240
Synthesis of Urea 1828 started Organic medicinal Chemistry
Ehrlich’s “Side chain theory” and chemotherapy and Fischer’s lock-and
key theory Birth of Modern Med Chem 1800
Medicinal chemistry received formal recognition in academic
pharmacy in 1932
5. Objective of medicinal chemistry !
Generally, we can identify the following stages in drug discovery, design and
development.
Drug discovery-finding a lead
• Choose a disease.
• Choose a drug target.
• Identify a bioassay.
• Find a lead compound.
• Isolate and purify the lead compound if necessary.
• Determine the structure of the lead compound if necessary.
Drug design
• Identify structure-activity relationships (SARs)
• Identify the pharmacophore.
• Improve target interactions (pharmacodynamics).
• Improve pharmacokinetic properties,
6. Drug development
• Patent the drug.
• Carry out preclinical trials (drug metabolism, toxicology, formulation and stability
test, pharmacology studies, etc).
• Design a manufacturing process (chemical and process development).
• Carry out clinical trials.
• Register and market the drug.
• Make money.
Finally Medicinal chemistry includes synthetic & computational aspects of the study
of existing drugs and agents in development in relation to their bioactivities i.e.,
understandings a SARs (Structure Activity Relationships). OR • Itisatailoring ofdrug
7. What is combitorial chemistry?
Combinatorial chemistry is a technique by which large numbers of
different but structurally similar molecules are produced rapidly and
submitted for pharmacological assay.
This technique uses the same reaction conditions with the same
reaction vessels to produce a large range of analogues.
Technique invented in the late 1980s and early 1990s to enable tasks to
be applied to many molecules simultaneously
8. Combitorial library
Def: collection of finally synthesized compounds
Size: depends on the number of building blocks used per reaction and the number of
reaction steps, in which a new building block is introduced
Typical: 102 up to 105 compounds
Random libraries Focused or targeted libraries
Multiple libraries Template –scaffold library
Multiple targets One target
Highly diverse Highly structural similarity
Mixtures Single compounds
˃ 5000 compounds ˂ ˂ 5000 compounds
Solid phase synthesis Synthesis in solution, solid phase
Non purified compounds Pure compounds
On bead screening, if possible Screening in solution
9. Applications
Applications of combinatorial chemistry are very wide Scientists use combinatorial
chemistry to create large populations of molecules that can be screened efficiently.
By producing larger, more diverse compound libraries, companies increase the
probability that they will find novel compounds of significant therapeutic and
commercial value.
Provides a stimulus for robot-controlled and immobilization strategies that allow
high-thrughput and multiple parallel approaches to drug discovery.
10. Techniques in combitorial chemistry
Solid support synthesis: (on solid phase such as resin bead, pins, or chips)
Split and mix method
Parallel synthesis
Solution phase synthesis (in solvent in the reaction flask
Solid phase synthesis
Reactants are bound to a polymeric surface and modified whilst still attached. Final
product is released at the end of the synthesis.
Examples of solid phase supports:
Partially cross-linked polystyrene beads hydrophobic in nature causes
problems in peptide synthesis due to peptide folding
Sheppard’s polyamide resin - more polar
Tentagel resin - similar environment to ether or THF
Beads, pins and functionalized glass surfaces
11. Method
• Beads must be able to swell in the solvent used, and remain stable
• Most reactions occur in the bead interior
L
Anchor or linker
A molecular moiety which is covalently attached to the solid support, and
which contains a reactive functional group
• Allows attachment of the first reactant
• The link must be stable to the reaction conditions in the synthesis but easily
cleaved to release the final compound
• Different linkers are available depending on the functional group to be
attached and the desired functional group on the product
• Resins are named to define the linker e.g. Merrifield, Wang, Rink
12. Solid phase synthesis: protecting groups
A few protecting groups used in solid phase synthesis.
For amines:
Boc ( t-butoxycarbonyl )
Fmoc (9-fluorenylmetoxy carbonyl)
Tmsec (2 [trimethylsilyl] ethoxycarbonyl)
For carboxylic acids:
Tert Bu ester(t-butyl ester)
Fm ester(9-fluronyl methyl ester)
Tmse ester(2 [trimethylsilyl] ethyl)
13. Parallel Synthesis
To use a standard synthetic route to produce a range of analogues, with a different
analogue in each reaction vessel, tube or well.
The identity of each structure is known
Useful for producing a range of analogues for SAR or drug optimisation.
Procedure for parallel synthesis!
Houghton’s Tea Bag Procedure:
Each tea bag contains beads and is labelled
Separate reactions are carried out on each tea bag
Combine tea bags for common reactions or work up procedures
A single product is synthesised within each teabag
Different products are formed in different teabags
Economy of effort - e.g. combining tea bags for workups
Cheap and possible for any lab
Manual procedure and is not suitable for producing large quantities of different
products
14. Automated parallel synthesis:
Automated synthesizers are available with 42, 96 or 144 reaction vessels or wells
Use beads or pins for solid phase support
Reactions and work ups are carried out automatically
Same synthetic route used for each vessel, but different reagents
Different product obtained per vessel
15. Mixed Combinatorial Synthesis:
To use a standard synthetic route to produce a large variety of
different analogues where each reaction vessel or tube contains a
mixture of products
The identities of the structures in each vessel are not known with
certainty
Useful for finding a lead compound
Capable of synthesizing large numbers of compounds quickly
Each mixture is tested for activity as the mixture Inactive mixtures
are stored in combinatorial libraries
Active mixtures are studied further to identify active component
16. The Mix and Split Method:
Example - Synthesis of all possible dipeptides using 5 amino acids
Standard methods would involve 25 separate syntheses.
Combinatorial procedure involves five separate syntheses using a mix
and split strategy
17. Quantitative structure activity relationship
(QSAR)
QSAR is a mathematical relationship in the form of an equation
between the biological activity and measurable physiochemical
parameters.
QSAR attempts to identify and quantify the physicochemical
properties of a drug and to see whether any of these property has an
effect on the drugs biological activity
The parameters used in QSAR is a measure of the potential
contribution of its group to a particular property of the parent drug.
Activity is expressed as log(1/C). C is the minimum concentration
required to cause a defined biological response.
18. Various parameters used in QSAR studies are
Lipophilic parameters: partition coefficient, π- substitution constant.
Electronic parameters: Hammet constant.
Steric parameters: Taft’s constant, molar refractivity, Verloop steric
parameter.
LIPOPHILIC PARAMETERS
Lipophilicity is partitioning of the compound between an aqueous and
non-aqueous phase.
Partition coefficient: P=[drug] in octanol/[drug] in water
20. π-substituent constant or hydrophobic substituent constants:
The π-substituent constant defined by Hansch and co-workers.
Measure of how hydrophobic a substituent is, relative to H.
Positive values imply substituents are more hydrophobic than H
Negative values imply substituents are less hydrophobic than H
A QSAR equation may include both P and p.
P measures the importance of a molecule’s overall hydrophobicity (relevant to
absorption, binding etc.)
p identifies specific regions of the molecule which might interact with hydrophobic
22. σ value depends on inductive and resonance effects
σ value depends on whether the substituent is meta or para
ortho values are invalid due to steric factors
23. STERIC SUBSTITUTION CONSTANT
It is a measure of the bulkiness of the group it represents and it effects
on the closeness of contact between the drug and receptor site. It is
much harder to quantitate.
Taft’s steric factor (Es') : Measured by comparing the rates of
hydrolysis of substituted aliphatic esters against a standard ester under
acidic conditions
Es = log kx - log ko
kx represents the rate of hydrolysis of a substituted ester
ko represents the rate of hydrolysis of the parent ester
24. Molar refractivity (MR): Measure of the volume occupied by an atom or group--
equation includes the MW, density(d), and the index of refraction
(n)– MR=(n²-1)MW/(n²+2)d
Verloop steric parameter: computer program uses bond angles, van der Waals radii,
bond lengths.
Hansch Equation
A QSAR equation relating various physicochemical properties to the biological
activity of a series of compounds
Usually includes log P, electronic and steric factors
Start with simple equations and elaborate as more structures are synthesised
Typical equation for a wide range of log P is parabolic
25. Conclusions:
• Activity increases if p is +ve (i.e. hydrophobic substituents)
• Activity increases if s is negative (i.e. e-donating substituents)