Dr. Vipul M.
Vaghela
Professor,
Department of Pharm. Chemistry,
A. R. College of Pharmacy,
Vallabh Vidyanagar,
February 14, 2024 Anand, Gujarat. 1
Flow of my presentation
• Why new drugs?
• Ideal drug
• Overview of Drug Discovery and Development Process
• Why Structure Activity Relationship (SAR)?
• SAR in Drug Design
• Quantitative Structure Activity Relationship (QSAR)
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Why need new Drug ?
• Unmet medical need
• New Diseases (Alzheimer's, Obesity, Covid-
19…)
• Drug Resistance (Antibiotics….)
• Low efficacy (Cancer, Dementia…)
• Side and adverse effects (Safety issues)
Banned drugs…..
• Cost of therapy (Cancer, Depression…)
• Patent expiry…..
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Aim of Healthcare Profession……..
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Background:
Neurotransmitters and Endogenous chemicals: Acetylcholine,
Adrenaline, Noradrenaline, Dopamine, GABA, Serotonin etc…
Drug: Agonist, Antagonist, Enzyme inhibitors, Enzyme activators etc…
Drug Target: Receptors, Enzyme, ion channels, cell wall, nucleus
(DNA, RNA..) etc…
Stereochemistry: Study of compounds in 3D.
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Forces involved between drug and target:
Electrostatic or ionic bonds:
Hydrogen bonds:
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Vander waals and hydrophobic interactions:
Dipole-dipole interactions:
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Lipinski’s rule of five
The orally administered drug must not have:
A molecular weight > 500 Dalton
LogP > 5
H-bond donor > 5
H-bond acceptor > 10
There are some exceptions out of this rule:
Drugs that have specific transporters such as
peptidomimetic agents.
Drugs targeting CNS should have:
H-bond donor ≤ 3
H-bond acceptor ≤ 6
Drug Discovery and Development Process
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Discovery Stage
Choose Disease Target selection
Studies of Target
Disease Mechanisms -receptor; -ion channel; -transporter;
-enzyme; - signalling molecule
Target Identify
validation Bioassay
Animal Studies
- relevant species
- agonists/antagonists
- antibodies
- RNAi
Molecular Studies
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Discovery stage
Lead Discovery (Traditional methods)
• structure that has some activity against the target, but not yet good
enough to be the drug itself.
Using Someone Else’s Lead
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Lead Discovery (Rational methods)
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Lead optimization (Drug Design)
Medicinal chemistry driven optimization
Combinatorial chemistry and High throughput
screening (library of compounds)
Structure Activity Relationship
Pharmacophore and auxophore
QSAR
X-ray crystallography and protein databank
Docking
ADME profiling (bioavailability)
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Development Stage
Process R&D
Pre-Clinical Chem Eng. R&D
Pharmacology Manufacturing
Animal Study
Drug Metabolism
(ADME)
Bio Process R&D
Pharmaceutical R&D
Formulation
Regulatory Affairs
IND (Investigational New Drug)
Statistics & Epidemiology
Data Coordination
Information Services
Clinical
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Phase I
Investigational
20 - 100 healthy volunteers take
New Drug drug for about one month
application Safety and tolerability studies
on healthy volunteers
IND Duration: about 1 year
Clinical
Phase II Clinical studies to
Trials Several hundred health-impaired patients demonstrate proof of
Treatment Group Control Group concept and dose
findings
Duration: about 2 years
Phase III
Hundreds or thousands of health- Efficacy and safety
impaired patients
studies on large number
of subjects
Duration: about 3 years
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Clinical
Trials Advisory
Committee
Regulatory
Review Team
Continued
APPROVAL
PROCESS
(Ex. FDA)
Submit to
Regulatory Agencies
New Drug
Application
(NDA)
APPROVAL
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Launch and Market
the Drug
Make Money….
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If fails at any stage than
big loss to company
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Drug Design tools
Virtual screening
AR Leach, VJ Gillet, An Introduction to Cheminformatics
Medicinal Chemistry
The science that deals with the discovery or
design of new therapeutic agents and their
development into useful medicines.
It involves:
• Synthesis
• Structure-Activity Relationships (SAR)
• Receptor interactions
• Absorption, distribution, metabolism, and
excretion (ADME)
Lead modification
The aim here is to improve the desired properties in
the lead compound and try to reduce the toxic or
unfavorable effects.
The first step in this process is to identify the
PHARMACOPHORE.
Pharmacophore is a collection of groups in the
molecule that interact with the receptor or the
enzyme and are responsible for activity
Molecular Docking;
Pharmacophore and Auxophore
Auxophore: is the groups rather than the
pharmacophore in the chemical structure.
Many roles have been identified for the auxophore:
Hold the pharmacophoric groups in their place.
Interfere with the binding to the receptor…
un-favorable.
Occupy an inert space.
Affect the pharmacokinetic properties of the whole
structure.
Lead modification
The second step in the lead modification is the
functional group modification depending on the study
of the pharmacophore.
Example: sulfonamide lead modification:
This is the antibacterial
pharmacophore
This is the hypoglycemic
pharmacophore
Structural modification
The main aim is to get more active, potent and safer
agents compared to the lead compound.
Methods for structural modification:
Homologation: is to lengthen the alkyl chain in the
chemical structure by CH2:
Chain length up to 9 carbon atom….tolerable (optimum
lipophilicity and water solubility.
Chain length more than 9 carbon atoms…low water
solubility… low availability.
Chain branching:
alkyl branching will lower the lipophilicity.
Alkyl branching will weaken the binding with the biological
target.
Ring chain transformation:
Affects both lipophilicity and drug metabolism
Ring expansion/Ring contraction
Change of position of substituent: Increase in bulk
Chain expansion/contraction:
Molecular Disconnection /Simplification
[email protected]
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