Pharmaceutical Chemistry in
Drug Discovery & Development
PCH 211
Department of Pharmaceutical Chemistry
Professor Chinedum Peace Babalola
Lecture Objectives
• Define pharmaceutical chemistry and explain its
relevance in pharmacy.
• Describe stages of drug discovery and
development.
• Explain medicinal chemistry’s role in rational
drug design.
• Analyze case studies of well-known drugs.
• Solve pharmaceutical problems in team-based
assignments.
What is Pharmaceutical Chemistry?
• Focuses on design, synthesis, and
development of drugs.
• Integrates organic chemistry, biochemistry,
pharmacology.
• Aims to discover and optimize therapeutic
agents.
Importance in Pharmacy
• Ensures safety, efficacy, and quality of drugs.
• Bridges chemistry and pharmacotherapy.
• Critical for understanding drug mechanism of
action.
DRUG DISCOVERY
• Drug discovery is a multidisciplinary process through which a potent new
therapeutic/drug molecule is identified to prevent/treat a particular disease
condition.
• It has a significant role in the practice of modern medicine and has emerged
as one of the main translational activities that contribute to human health
and well-being.
• The design and discovery of new therapeutic molecules for disease still relies
on trial-and-error methods and it involves a wide range of scientific
disciplines including biology, medicinal chemistry, structural biology,
pharmacology, etc.
• Many pharmaceutical industries, academia, and scientific communities
around the globe are actively involved in the search for new chemical entities
(drug molecules) for a wide variety of diseases.
• Discovery of a drug molecule (ligand) for a particular drug target (receptor,
enzyme, ion channel, transporter, protein–protein interactions, DNA, etc.) is
an expensive and time-consuming procedure that normally takes an average
of 10–15 years with an estimated cost of US$1 –3 Billion
Target identification
• The discovery of a new drug molecule is required for treating a disease or illness
for which no other treatment exists or provides additional advantages over
prevailing treatments such as lesser adverse effects, higher therapeutic efficacy,
improved amenability, and fewer drug–drug interactions, etc.
• A thorough understanding of disease biology especially the identification of
impaired biomolecule/drug target function that contributes to disease
pathology is very important for drug discovery process.
• Identification of a drug target is the first and foremost step in the drug
discovery and development process.
• Generally, drug targets are classified into two categories: one is
established/reported drug targets and the other is novel drug targets that are
yet to be identified.
• The functions and pathophysiological roles of the reported targets have already
been scientifically well studied and validated, while the novel target demands a
thorough understanding of its role and has to be validated as well.
• Several scientific methods including phenotype screening, genetic study,
transgenic animal, molecular, and functional imaging techniques are widely
employed for target identification and validation
DRUG TARGETS
NEW TARGETS
DRUG TARGETS
• Lipids: Cell Membrane Lipids Total Druggable
Genome genes
• Proteins: Receptors, Enzymes, Carrier Includes biological Space
Proteins, Structural Proteins (tubulin)
Small molecule Space
• Nucleic Acids: DNA, RNA New druggable space ?
• Carbohydrates: Cell surface Existing drugs targets
carbohydrates, Antigens and recognition targets)
molecules ~30,000 ~3,000
Genomics helps to identify new drug targets
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Stages of Drug Discovery
1. Target Identification & Validation
2. Hit Identification (Screening & Design)
3. Lead Optimization
4. Preclinical and Clinical Testing
5. Regulatory Approval & Post-Market
Surveillance
Drug Discovery & Development:
Drugs: Targets
:
Natural sources Synthetic sources
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Drug Discovery & Development : Genetic influence
Identify disease Genetic effects on drug response
Find a drug effective
against disease protein
Isolate protein (2-5 years)
involved in Scale-up
disease (2-5 years)
Genetic effects on drug disposition
Preclinical testing
(1-3 years) Human clinical trials
(2-10 years)
IN le
D
Fi
Genetic effects on drug disposition
A
ND
Formulation
le
Fi
FDA approval
(2-3 years)
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Technology in Drug Discovery
GENOMICS, PROTEOMICS & BIOPHARM.
Potentially producing many more targets
and “personalized” targets
HIGH THROUGHPUT SCREENING
Identify disease Screening up to 100,000 compounds a
day for activity against a target protein
VIRTUAL SCREENING
Using a computer to
Isolate protein predict activity
COMBINATORIAL CHEMISTRY
Rapidly producing vast numbers Find drug
of compounds
MOLECULAR MODELING
Computer graphics & models help improve activity
Preclinical testing
IN VITRO & IN SILICO ADME MODELS
Tissue and computer models begin to replace animal testing
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TARGET SELECTIVITY Within the body
• Selectivity between different enzymes,
Between species receptors etc.
• Antibacterial and antiviral agents • Selectivity between receptor types and
• Identify targets which are unique to the subtypes
invading pathogen • Selectivity between isozymes
• Identify targets which are shared but which • Organ selectivity
are significantly different in structure
DRUG TESTING
• Tests are required in order to find lead
compounds and for drug optimisation
• Tests can be in vivo or in vitro
• A combination of tests is often used in
research programmes
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DRUG DISCOVERY PROCESS
Target
Identification and Validation Lead
Compounds
Evaluation
Chemical Libraries,
Combichem, Clinical Trials
Natural Products
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Drug Discovery (LI & LO)
• Lead discovery (LI). Identification of a compound that triggers specific biological
actions.
• Lead optimization (LO). Properties of the lead are tested with biological assays; new
molecules are designed and synthesized to obtain the desired properties
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Gene or Genome
Target Target Lead Pre- Clinical Clinical Clinical Manufac
Sequencing
Discovery Validation Discovery Clinical Phase I Phase II Phase III -turing
Distribution
Drug Discovery Animal Clinical Tests Commercialization
Studies
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Principles of Medicinal Chemistry
A. HIT Identification
• High-Throughput Screening (HTS)
– Hundreds of thousands of compounds tested against a biological assay (e.g.,
enzyme inhibition).
– Pros: Can uncover unexpected chemotypes.
– Cons: Expensive; many false positives.
• Fragment-Based Drug Design (FBDD)
– Screen small fragments (MW 150–250 Da) for weak binding (mM–µM).
– Grow or link fragments to improve binding.
– Example: Vemurafenib (BRAF inhibitor), grew fragments guided by X-ray
crystallography.
• Virtual Screening
– Computational docking of large libraries into a crystal structure or model of the
target.
– Key point: Hits must still be synthesized and tested experimentally.
B. LEAD OPTIMIZATION
What’s a Lead?
– A compound with confirmed activity (e.g., IC₅₀ < 1 µM) but suboptimal
properties.
• Medicinal-Chemistry Goals
– Potency & Selectivity
• Improve binding to target vs. off-targets.
• Use bioisosteric replacements (e.g., replace a phenol with a pyridine).
– Physicochemical Properties
• Lipophilicity (log P): Aim for log P ~1–3 for oral drugs.
• Polar Surface Area (PSA): PSA < 140 Ų for good oral absorption; < 90 Ų for
blood–brain barrier penetration.
– Lipinski’s Rule of Five
• MW ≤ 500; log P ≤ 5; H-bond donors ≤ 5; H-bond acceptors ≤ 10.
• Rule‐breakers exist (e.g., antibiotics, natural products), but it’s a useful
guideline.
C. Molecular Design Strategies & SAR
A. Structure–Activity B. Molecular Modeling
Relationships (SAR)
Tools (screenshots/demos)
• Definition: Systematic
modification of a core scaffold • Docking software (e.g.,
to see how changes affect AutoDock Vina) to
biological activity.
predict binding modes.
• Example Case Study
– Start with a simple aniline that • Pharmacophore
inhibits a kinase at IC₅₀ = 10 µM. modeling to identify key
– Introduce a para-methoxy group
→ potency improves to 1 µM.
interactions (H-bond
– Replace para-methoxy with para- donor/acceptor,
fluoro → potency 0.5 µM, but
reduces metabolic liability.
hydrophobic regions).
Physicochemical Properties
1. Physicochemical properties 2. Drug–Target Interactions
• Molecular Weight (MW) • Non-covalent Forces
– Optimal for oral drugs: ≤ 500 Da – Hydrogen bonds (donor ↔ acceptor)
– Heavier molecules often have poor – Ionic interactions (charged groups)
absorption and distribution – Hydrophobic contacts (aromatic rings,
• Lipophilicity (log P / log D) aliphatic chains)
– Balances membrane permeability vs. – π–π stacking (between aromatic
water solubility systems)
– Ideal oral range: log P ~1–3 • Pharmacophore Concepts
• Polarity & Polar Surface Area (PSA) – Abstract map of essential features (H-
– PSA < 140 Ų for intestinal absorption; < bond donors/acceptors, hydrophobic
90 Ų for blood–brain barrier penetration regions, positive/negative ionizable
sites) required for activity
• pKa and Ionization
– Determines ionized vs. neutral form at
• Binding Affinity & Selectivity
physiological pH – Measured by Ki, IC₅₀, Kd
– Influences solubility, permeability and – Selectivity achieved by optimizing
distribution complementary interactions in the
target’s binding pocket
3. Structure–Activity Relationships 4. Stereochemistry
(SAR) • Chirality
• Systematic Modification
– Change one part of the molecule at
– Enantiomers can have
a time (e.g., replace –OH with – dramatically different
OCH₃) potency, safety, or
• Bioisosterism metabolism
– Exchange of chemically or physically
similar groups (e.g., –OH ↔ –SH or – Example: (S)-ibuprofen is
carboxylic acid ↔ tetrazole) to the active form
improve potency, selectivity, or
metabolic stability • Conformational Analysis
• Lead Optimization Cycle – Rigid vs. flexible scaffolds
– Synthesize analogues
– Test biological activity
affect binding entropy
– Analyze SAR trends and specificity
– Refine scaffold •
More on Structure-Activity Relationship
(SAR)
• Relates chemical structure to biological
activity.
• Modifications improve efficacy, selectivity,
safety.
• Key to optimizing drug molecules.
5. Prodrugs & Analog Design
Prodrugs & Drug Delivery
– Inactive derivatives that convert in vivo to the
active drug (e.g., enalapril → enalaprilat, Proguanil
to cycloguanil)
• Formulation Strategies
– Salt forms, co-crystals, and lipid-based systems to
enhance solubility or permeability
• Analog design: Modify existing drugs to
improve properties.
6. ADMET
6. ADMET (Absorption, Distribution,
Metabolism, Excretion, Toxicity)
• Absorption
– Passive diffusion vs. transporter-mediated
uptake
– Caco-2 and PAMPA assays for permeability
• Distribution
– Plasma protein binding (binders vs. free drug)
– Volume of distribution (Vd)
• Metabolism
– Phase I (oxidation, reduction, hydrolysis)
primarily by CYP450s
– Phase II (conjugation: glucuronidation,
sulfation, etc.)
• Excretion
– Renal (glomerular filtration, tubular secretion)
vs. biliary routes Pharmacokinetics (PK) – is the rate processes
• Toxicity or characterization or quantification of time
– Off-target liabilities (hERG inhibition, reactive course of drug absorption, distribution,
metabolite formation) metabolism and excretion popularly referred to
– Genotoxicity (Ames test), organ-specific as ADME or LADME.
assays
ADMET
Computer-aided drug discovery (CADD) for Lead
Discovery and Development
• Lead discovery and development involves the identification of a synthetic or natural chemical
molecule/peptide/antibody that specifically and efficiently binds to a drug target and thereby
modulates its biological function.
• Lead molecules (also referred to as hit) could be considered as a prototype, from which the
drug molecules are developed.
• The initial step in lead discovery is to identify a starting molecule that shows reasonable
biological activity toward the target protein.
• Both experimental and computational methods are widely used for lead identification and
optimization as well.
• Some of the extensively used experimental methods that are being used for hit identification
include high-throughput screening (HTS), combinatorial library screening, knowledge-based
screening, fragment-based screening etc.
• HTS is a well-defined and widely used experimental method in which tens and thousands of
chemical entities are screened in an assay system (i.e., cell/enzyme-based assay) against the
target protein to find starting chemical compounds with anticipated biological activity
• In combinatorial screening a large number of structurally diverse or focused
library compounds are being synthesized through systematic covalent
linkage of various building blocks and are subjected to screening against
particular drug target to know their positive interaction with the target
protein.
• Furthermore, the identified positive hits are evaluated for lead development
and optimization. In fragment-based screening, thousands of chemical
fragments are evaluated for biological activity with the desired target protein
using biochemical and biophysical methods.
• Hit identification using experimental methods is expensive and time-
consuming as they require extensive development and validation of complex
assay systems.
• Alternatively, computational methods commonly known as CADD techniques
such as virtual screening (VS) methods have emerged as powerful
techniques for hit identification (Lionta et al., 2014; Wang et al., 2020).
• In VS experiments, a molecular library consisting of millions of
chemical molecules is screened computationally (in silico) in a
short time and the compounds which are predicted as
active/positive are then subjected for further biological testing.
• The filtered inactive/negative compounds are skipped from
biological testing.
• This VS strategy for lead identification significantly reduces the
cost and workload as compared to HTS screening .
• Once a lead molecule is identified with the desired biological
activity, it undergoes several rounds of chemical optimization
(analog synthesis) to improve the pharmacokinetics,
pharmacodynamics, and toxicity profile.
From Candidate to Clinic
A. Preclinical to Clinical Transition B. Regulatory Highlights
• Toxicology Battery • Investigational New Drug (IND)
– Acute, sub-acute, chronic studies in Application
two species (rodent + non-rodent). – CMC: Chemistry, Manufacturing &
– Safety pharmacology (CV, respiratory, Controls section.
CNS). – Pharmacology/Toxicology:
• Formulation Chemistry Preclinical study reports.
– Solid oral—salt selection, polymorph – Clinical Protocol: Phase I study
screens, dissolution testing. design, dosing rationale, safety
– Parenteral—solubility enhancers, monitoring.
stability. • ICH Guidelines Overview
• GMP Synthesis – Q1: Stability testing
– Scale-up from milligrams to – Q2: Analytical method validation
kilograms. – Q3: Impurities
– Impurity control and analytical – … through Q12 (lifecycle
methods (HPLC, GC). management)
Case Studies
Suggested Case Studies
1. Penicillin
o Discovery, structure, resistance issues
o Ref: Fleming A. (1929). On the antibacterial action of cultures of a Penicillium.
2. Imatinib (Gleevec)
o Development for CML (Chronic Myeloid Leukemia)
o Ref: Druker BJ, et al. (2001). Efficacy and safety of a specific inhibitor of the
BCR-ABL tyrosine kinase in chronic myeloid leukemia.
3. Atorvastatin (Lipitor)
o Rational drug design process
o Ref: Roth BD. (2002). The discovery and development of atorvastatin.
CASES
Omeprazole (proton-pump inhibitor)
– Hit: substituted benzimidazole
scaffold active against H⁺/K⁺-
ATPase.
– Lead Optimization: introduction of
sulfoxide moiety for acid-stability
and stereo-control.
– ADMET: improved oral
bioavailability via enteric coating
to avoid stomach degradation.
– Preclinical Safety: reversible liver
enzyme elevations required dose
adjustments.
– Clinical Success: market launch in
1989; multiple follow-on patents
for delayed-release forms.
Penicillin Atorvastatin (Lipitor)
• Discovered by • Designed to inhibit
Alexander Fleming HMG-CoA reductase.
(1928). • • Statin class for
• • Inhibits bacterial cell hyperlipidemia.
wall synthesis. • • Structure-based
• • Basis for β-lactam rational drug design.
antibiotics
Imatinib (Gleevec)
• • Inhibits BCR-ABL tyrosine kinase in Chronic
Myeloid (Myelogenous) Leukemia (CML)
• • First successful targeted cancer therapy.
• • Example of personalized medicine.
• Search more information
Case Study – Imatinib (Gleevec)
• Targets BCR-ABL fusion
gene in leukemia
• FDA approved 2001
• First success of “targeted
therapy”
1.
Assignments
What is the significance of SAR in medicinal chemistry?
2. Match the drug to its mechanism of action:
o a) Imatinib
o b) Penicillin
o c) Atorvastatin
o Options: i. Inhibits bacterial cell wall synthesis ii. Inhibits BCR-ABL kinase iii. Inhibits HMG-CoA
reductase
3. Explain the concept of a prodrug and give one example.
Discussion Questions
4. How can pharmaceutical chemistry reduce drug development failure rates?
5. What ethical considerations must be addressed in drug design?
6. In what ways can computational chemistry aid modern drug discovery?
Individual Assignment
• • Write a 2-page SAR analysis on:
• • Aspirin
• • Captopril
• • Omeprazole
• • Due in one week.
Quiz and Discussions
Sample Quiz Questions
• • What is a pharmacophore?
• • Match drugs to their mechanisms of action.
• • Explain what a prodrug is, with an example.
Watch These Videos
• https://
youtu.be/3Gl0gAcW8rw?si=GoSxTze9EdSKJyGI
• https://
youtu.be/e-Wksw9hjh0?si=YOU2LkvbLTQfMeu
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