KALYAN POST GRADUATE COLLEGE, BHILAI

Department of Chemistry

UNIT NOTES

Drug Design & Development

Lead Compounds & Lead Modification

[Link]. Chemistry | Medicinal Chemistry

Based on: Medicinal Chemistry — Alka L. Gupta & V. Alagarsamy

Course Medicinal Chemistry II

Compiled Dept. of Chemistry, Kalyan PG College

Session 2025–26

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 TABLE OF CONTENTS

1. Drug Design and Development — Overview

2. New Drug Development — Stages and Process
3. Procedures Followed in Drug Design
3.1 Target Identification and Validation
3.2 Hit Discovery
3.3 Lead Identification
3.4 Lead Optimisation
3.5 Preclinical Development
3.6 Clinical Trials (Phase I–III)
3.7 Regulatory Approval and Post-Marketing
4. Lead Compounds — Concept and Sources
4.1 Definition of Lead Compound
4.2 Sources of Lead Compounds
4.3 Criteria for a Good Lead
4.4 Hit-to-Lead Progression
5. Lead Modification
5.1 Bioisosterism
5.2 Prodrug Design
5.3 Scaffold Hopping
5.4 Fragment-Based Drug Design
5.5 Structure-Activity Relationship (SAR)
5.6 Lipinski's Rule of Five and Drug-likeness
6. Important Definitions at a Glance
7. Reference Books

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 UNIT 1 — DRUG DESIGN AND DEVELOPMENT — OVERVIEW

1.1 Introduction
Drug design and development is the process by which a biologically active molecule is identified,
optimised, and eventually transformed into a therapeutic agent suitable for human use. It represents the
intersection of medicinal chemistry, pharmacology, molecular biology, and clinical medicine.
The modern drug discovery pipeline is an enormously complex, expensive, and time-consuming
enterprise. On average, it takes 10–15 years and an investment of USD 1–2 billion to bring a single
new chemical entity (NCE) from initial discovery to the pharmacy shelf. Across thousands of candidate
molecules screened, only 1 in 10,000 will ultimately reach market approval.

1.2 Goals of Drug Design

• Selectivity: The drug should act on a specific biological target with minimal interaction with
off-targets to reduce adverse effects.
• Potency: Adequate binding affinity for the target at therapeutically meaningful concentrations.
• Pharmacokinetic suitability: Favourable Absorption, Distribution, Metabolism, Excretion, and
Toxicity (ADMET) profile.
• Chemical stability: The molecule must be chemically and metabolically stable under physiological
conditions.
• Patentability and manufacturability: The molecule must be novel and synthesisable on a large
scale at reasonable cost.

1.3 Rational Drug Design vs. Random Screening

Rational Drug Design Random / Empirical Screening

Based on known 3D structure Large libraries of natural or synthetic compounds screened

of the biological target against a biological assay without prior structural knowledge
(structure-based) or known
ligand properties
(ligand-based)

Examples: HIV protease Examples: penicillin (serendipitous), aspirin (folk medicine)

inhibitors, statins

Faster, more directed; requires Less directed; requires high-throughput screening (HTS)
detailed structural data infrastructure

1.4 Types of Drug Design Approaches

A. Structure-Based Drug Design (SBDD)
Uses the three-dimensional structure of the biological target — obtained via X-ray crystallography,
NMR, or cryo-electron microscopy — to design molecules that fit into the active site. Computational
docking, molecular dynamics simulations, and de novo drug design programs (e.g., AutoDock, Glide,
MOE) are employed.
• Key tools: X-ray crystallography, NMR spectroscopy, cryo-EM, molecular docking, pharmacophore
modelling.

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 • Example: Design of saquinavir and other HIV protease inhibitors by fitting molecules into the
enzyme's active site.

B. Ligand-Based Drug Design (LBDD)

When the 3D structure of the target is unavailable, the known active ligands are used to build a
pharmacophore model — a 3D representation of the features required for biological activity. QSAR
(Quantitative Structure-Activity Relationship) analysis is a key component.
• Key tools: Pharmacophore modelling, QSAR, 3D-QSAR (CoMFA, CoMSIA), virtual screening.
• Example: Design of H2-receptor antagonists like cimetidine based on histamine scaffold.

C. Fragment-Based Drug Design (FBDD)

Small molecular fragments (MW < 300 Da) with weak but measurable binding are identified and then
grown, linked, or merged to produce high-affinity leads. Fragment screening uses biophysical
techniques such as SPR, NMR, or X-ray crystallography.

D. Computational / In Silico Drug Design

Encompasses virtual screening of large compound databases, homology modelling of target structures,
quantum mechanical calculations to predict binding energies, and machine learning / artificial
intelligence tools for property prediction and de novo molecule generation.

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 UNIT 2 — NEW DRUG DEVELOPMENT — STAGES AND PROCESS

2.1 Overview of the Drug Development Pipeline

The drug development process can be broadly divided into two phases: Drug Discovery (pre-clinical)
and Drug Development (clinical and regulatory). The pre-clinical phase involves target identification,
lead discovery, and lead optimisation; the clinical phase covers human trials and regulatory approval.

Key Stages at a Glance

• Stage 1: Target Identification and Validation

• Stage 2: Hit Discovery (HTS / Virtual Screening)

• Stage 3: Hit-to-Lead (H2L) Progression

• Stage 4: Lead Optimisation (LO)

• Stage 5: Preclinical Development (ADMET, Toxicology)

• Stage 6: Investigational New Drug (IND) Application

• Stage 7: Clinical Trials — Phase I, II, III

• Stage 8: New Drug Application (NDA) / Regulatory Approval

• Stage 9: Post-Marketing Surveillance (Phase IV)

2.2 Target Identification and Validation

A drug target is a biomolecule — typically a protein (enzyme, receptor, ion channel, or transporter) —
whose modulation produces a desired therapeutic effect. Identification is achieved through:
• Genomics, proteomics, and transcriptomics data (disease vs. normal tissue comparisons)
• Genetic evidence — GWAS studies linking gene variants to disease
• Phenotypic studies — observing the effect of gene knockout/knockdown in model organisms

Target validation confirms that modulation of the target produces the desired therapeutic effect without
unacceptable toxicity. Methods include: antisense oligonucleotides, siRNA knockdown, transgenic
animal models, and tool compounds.
Common target classes: Enzymes (e.g., COX, ACE, HMG-CoA reductase), GPCRs (G-protein coupled
receptors; ~34% of all approved drugs act on GPCRs), Ion channels (voltage-gated Na+/K+ channels),
Nuclear receptors (e.g., glucocorticoid receptor), and Kinases.

2.3 Hit Discovery

A hit is a compound that shows confirmed activity against the target in an initial screening assay,
reproducibly, and with reasonable potency. Hit discovery strategies include:
1. High-Throughput Screening (HTS): Automated robotic screening of large chemical libraries
(105–106 compounds) against the target using miniaturised assay formats (96-, 384-, or 1536-well
plates). Reporter assays, fluorescence polarisation, FRET, and luminescence are common
readouts.

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 2. Virtual Screening (VS): In silico docking of large compound databases into the target's crystal
structure to rank compounds by predicted binding affinity, followed by experimental confirmation of
top-ranked compounds.
3. DNA-encoded chemical libraries (DEL): Large combinatorial libraries where each compound is
tagged with a unique DNA barcode, enabling selection of binders from pools of billions of molecules.
4. Natural product screening: Extracts from plants, marine organisms, and microbes are screened;
bioassay-guided fractionation isolates the active component.

A hit is distinguished from a lead by: (a) confirmed potency (IC50 or Ki < 10 µM), (b) structure-activity
relationship (SAR) information, and (c) preliminary assessment of selectivity and physicochemical
properties.

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 UNIT 3 — PROCEDURES FOLLOWED IN DRUG DESIGN

3.1 The Drug Design Workflow

Drug design follows a systematic, iterative workflow involving biology, chemistry, pharmacology, and
computation. Each cycle tightens potency, selectivity, and ADMET properties while reducing attrition
risk.

Step 1: Define the Biological Hypothesis

Before any chemistry begins, the medicinal chemist must understand:
• The pathophysiology of the disease
• The mechanism by which modulating the target would produce benefit
• The nature of the binding site — orthosteric (active site) or allosteric
• Whether inhibition, agonism, partial agonism, or antagonism is desired

Step 2: Obtain Target Structure / Build Pharmacophore

If a co-crystal structure (target + known ligand) is available, the binding site geometry, key hydrogen
bond donors/acceptors, hydrophobic pockets, and electrostatic features are analysed. If no structure is
available, a pharmacophore is built from the known active compounds using CoMFA/CoMSIA or
pharmacophore modelling software.
• Pharmacophore features: Hydrogen bond donor (HBD), hydrogen bond acceptor (HBA),
hydrophobic centre (HYD), positive ionisable (PI), negative ionisable (NI), aromatic ring (AR).

Step 3: Virtual Screening / De Novo Design

Large compound databases (ZINC, ChEMBL, Enamine) are docked into the target and ranked.
Alternatively, de novo design algorithms construct molecules atom-by-atom within the binding site to
maximise predicted fit. Top candidates are filtered by:
• Predicted binding energy (∆G)
• Lipinski's Rule of Five (drug-likeness)
• Predicted ADMET liabilities (e.g., hERG cardiotoxicity, CYP inhibition, BBB permeability)

Step 4: Synthesis and Biological Evaluation

Shortlisted compounds are synthesised and tested in:
• Primary biochemical assay: Enzyme inhibition (IC50), receptor binding (Ki), or functional assay
(EC50).
• Counter-screen / selectivity panel: Activity against off-target proteins to assess selectivity.
• Cell-based assay: Cellular activity, cytotoxicity (CC50), and selectivity index (SI = CC50/EC50).

Step 5: ADMET Profiling

Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties are assessed
concurrently with potency optimisation. Key assays:

ADMET Parameter Experimental Assessment

Solubility (Absorption) Kinetic / thermodynamic solubility assays (nephelometry,

miniaturised shake-flask)

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 Permeability (Absorption) Caco-2 cell monolayer, PAMPA (parallel artificial membrane
permeability assay)

Plasma protein binding Equilibrium dialysis or ultracentrifugation

Metabolic stability Human/rat liver microsomes (HLM/RLM) incubation; intrinsic

clearance

CYP inhibition CYP3A4, 2D6, 2C9 fluorescence/LC-MS assay

hERG inhibition Patch-clamp electrophysiology; hERG channel binding assay

Genotoxicity Ames test, micronucleus assay

Acute toxicity In vitro MTT/LDH assay; in vivo LD50

Step 6: Lead Optimisation (Iterative Cycles)

Based on SAR data, ADMET results, and selectivity profiles, the chemist systematically modifies the
lead scaffold to improve the overall profile. This involves bioisosteric replacement, introduction of
metabolic blocking groups, rigidification, pro-drug strategies, and stereochemical modification. Each
cycle generates 20–50 new analogues for testing.

Step 7: Candidate Nomination and Preclinical Package

Once a molecule meets pre-defined criteria (potency, selectivity, metabolic stability, oral bioavailability,
acceptable toxicity), it is designated as a Development Candidate (DC). The preclinical package
includes:
• In vivo pharmacokinetics (PK) in rat, mouse, dog
• In vivo pharmacodynamic (PD) efficacy in disease models
• Safety pharmacology (CNS, cardiovascular, respiratory effects)
• GLP toxicology studies (14-day or 28-day repeat dose)
• Genotoxicity battery (Ames, MN, in vitro chromosomal aberration)

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 3.2 Clinical Development Stages
Once an Investigational New Drug (IND) application is approved by the regulatory authority (CDSCO in
India; FDA in USA; EMA in EU), human clinical trials begin.

Phase Key Objectives and Parameters

Phase I Safety, tolerability, PK, and dose range in 20–80 healthy volunteers (or
(First-in-Human) patients for oncology). Determines Maximum Tolerated Dose (MTD) and
Recommended Phase II Dose (RP2D).

Phase II Preliminary efficacy, dose–response, and safety in 100–300 patients.

(Proof-of-Concept) Identifies optimal dosing regimen. Subdivided into Phase IIa (POC) and IIb
(dose-finding).

Phase III (Pivotal Efficacy and safety vs. standard of care in large patient population
Trial) (300–3000+). Randomised, double-blind, controlled. Basis of regulatory
submission (NDA/MAA).

Phase IV Long-term safety surveillance, pharmacovigilance, detection of rare adverse

(Post-Marketing) effects, and expansion of labelling (new indications, special populations).

3.3 Regulatory Approval in India

In India, new drugs are regulated under the Drugs and Cosmetics Act, 1940 and the New Drugs and
Clinical Trials Rules, 2019. The Central Drugs Standard Control Organisation (CDSCO) is the apex
regulatory body. The key submissions include:
• IND (Investigational New Drug) application: Filed before Phase I/II; requires pre-clinical data,
proposed protocol, and investigator credentials.
• NDA (New Drug Application) / Marketing Authorisation: Filed after Phase III; comprehensive
dossier in CTD format comprising quality (CMC), safety, and efficacy data.
• IMPD (Investigational Medicinal Product Dossier): Quality and manufacturing data for
investigational drug supply.
Timeline from IND to approval in India typically ranges from 8–12 years. Expedited pathways (Fast
Track, Breakthrough designation) are available for unmet medical needs.

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 UNIT 4 — LEAD COMPOUNDS — CONCEPT AND SOURCES

4.1 Definition of a Lead Compound

A lead compound (or lead structure) is a chemical compound that:
• Demonstrates confirmed, reproducible biological activity against a defined target
• Shows a preliminary structure-activity relationship (SAR) — i.e., there is a chemical series with
modifiable positions
• Has reasonable physicochemical properties (solubility, permeability, MW) indicating potential for
optimisation
• Is chemically tractable — amenable to synthetic modification
• Displays acceptable selectivity — activity should preferably not be due to cytotoxicity or non-specific
membrane effects

A lead compound is distinct from a hit (the initial screen positive) in that it has been subjected to
additional characterisation — counter-screening, SAR exploration with at least 5–10 analogues,
solubility, permeability, and metabolic stability data. The progression from hit to lead is called
Hit-to-Lead (H2L) or Hit Confirmation and Expansion.

Typical Criteria for a Lead Compound (from Alka L. Gupta, Medicinal Chemistry)

• Potency: IC■■ or K_i < 1 µM in biochemical assay; EC■■ < 10 µM in cell assay

• MW ≤ 450–500 Da (to allow room for optimisation within Lipinski space)

• cLogP between 1 and 4 (lipophilicity within acceptable range)

• Aqueous solubility ≥ 10–50 µg/mL

• Metabolic stability: t½ > 30 minutes in HLM

• No Pan-Assay Interference Compounds (PAINS) alerts — no reactive groups

• Clean selectivity — no strong activity against major off-targets (hERG, kinase panel)

• Preliminary in vivo activity in at least one animal model (desirable)

4.2 Sources of Lead Compounds

Lead compounds are derived from diverse sources. The major categories are described below.

A. Natural Products
Natural products have historically been the most prolific source of leads and approved drugs. They offer
structural diversity far beyond typical synthetic libraries, with complex ring systems, multiple
stereocentres, and privileged scaffolds evolved over millions of years to bind biological macromolecules.
• Plants (Phytochemicals): Morphine (opiate analgesic) from Papaver somniferum; quinine
(antimalarial) from Cinchona bark; vincristine (anti-cancer) from Catharanthus roseus; reserpine
(antihypertensive) from Rauwolfia serpentina; salicin → aspirin.
• Microorganisms: Penicillin and cephalosporins (antibiotics) from Penicillium spp.; lovastatin
(cholesterol-lowering) from Aspergillus terreus; cyclosporin (immunosuppressant) from fungi;
rapamycin (mTOR inhibitor).

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 • Marine organisms: Ziconotide (pain; cone snail peptide); cytarabine (leukemia; sponge); eribulin
(cancer; sea hare).
• Animal products: Heparin (anticoagulant) from pig intestines; insulin from bovine/porcine pancreas
(originally); captopril lead compound from snake venom (bradykinin potentiating peptide).

B. Existing Drugs (Drug Repurposing / Repositioning)

An approved drug may serve as a lead for a new therapeutic indication. This strategy offers significant
advantages in terms of known safety profiles and reduced development timelines.
• Examples: Sildenafil (originally anti-anginal, → erectile dysfunction → pulmonary hypertension);
thalidomide (sedative → teratogen → multiple myeloma/leprosy); metformin (anti-diabetic →
potential anti-aging); aspirin (anti-inflammatory → anti-platelet).

C. Endogenous Ligands and Hormones

Neurotransmitters, hormones, and other endogenous substances that interact with the target can serve
as starting points for drug design.
• Examples: Adrenaline (epinephrine) → β-blockers (propranolol) and β-agonists (salbutamol);
histamine → H1/H2 antagonists; dopamine → antipsychotics; acetylcholine → muscarinic
agonists/antagonists.

D. Combinatorial Chemistry and HTS Libraries

Parallel and combinatorial synthesis generates large numbers of structurally related compounds
(arrays) or diverse compound collections. Coupled with HTS, this approach has been the dominant
source of hits since the 1990s.
• Diversity-oriented synthesis (DOS) generates sp3-rich, shape-diverse scaffolds
• Fragment libraries (MW 150–250) — screening with NMR, SPR, or X-ray
• DNA-encoded libraries (DELs) — selection-based screening of >109 compounds

E. Computational / Virtual Sources

Virtual screening of databases (e.g., ZINC15, PubChem, Enamine REAL Space containing >109
synthesisable compounds) using docking, pharmacophore matching, and ML-based models can identify
structurally novel leads with high efficiency.

F. Serendipitous Discovery
Some of history's most important drugs were discovered unexpectedly: penicillin (Fleming, 1928);
chlorpromazine (antihistamine → antipsychotic); iproniazid (anti-TB → antidepressant); cisplatin
(electrolysis experiment → anti-cancer).

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 4.3 Hit-to-Lead (H2L) Progression
The H2L process bridges the initial HTS hit and the validated lead compound. It involves:
1. Hit confirmation: Re-testing the original compound from independent stock;
concentration-response curves; orthogonal assays to confirm mechanism.
2. PAINS filtering: Removal of pan-assay interference compounds — reactive electrophiles,
aggregators, singlet oxygen generators, chelators that give artifactual signals.
3. Initial SAR: Synthesis of 10–30 close analogues to delineate essential vs. modifiable positions;
'SAR by catalogue' — purchase of commercially available analogues.
4. Property assessment: Aqueous solubility, Caco-2 permeability, microsomal stability, plasma
protein binding.
5. Selectivity screening: Activity against a selectivity panel (counterscreen, safety panel).
6. Decision: Only hits that pass all criteria are promoted to lead status for full optimisation.

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 UNIT 5 — LEAD MODIFICATION

Lead modification (also called lead optimisation) is the iterative process of chemical modification of the
lead compound to improve its potency, selectivity, bioavailability, and safety profile while maintaining or
enhancing its biological activity. It is the most time-intensive and chemistry-driven phase of drug
discovery.
The medicinal chemist uses a portfolio of strategies — bioisosteric replacement, prodrug design,
scaffold hopping, FBDD, and rigidification — guided by SAR data and molecular modelling.

5.1 Structure-Activity Relationship (SAR)

SAR is the foundation of lead modification. It is the systematic correlation between the chemical
structure of a compound and its biological activity. SAR is built by:
• Synthesising analogues with systematic structural changes (one change at a time — the 'SOSA'
approach)
• Measuring potency (IC50, EC50, Ki) for each analogue
• Mapping which structural features are essential (pharmacophoric) and which are modifiable
(decoratable)
SAR studies guide decisions on:
• Ring systems: Which ring size and heteroatom composition gives best potency/selectivity
• Substituents: Effect of electron-withdrawing (EWG) vs. electron-donating (EDG) groups, halogen
effects, methyl scanning
• Stereochemistry: Which enantiomer/diastereomer is active (eutomer vs. distomer); role of axial
chirality
• Chain length / flexibility: Optimal tether length between pharmacophoric groups

5.2 Bioisosterism
Bioisosteres are atoms or groups of atoms that have similar size, shape, electronic distribution, and
physicochemical properties and that produce broadly similar biological properties when substituted for
each other. Bioisosteric replacement is one of the most powerful tools in lead modification.

Classical Bioisosteres
Based on Langmuir's isosteric concept and Grimm's hydride displacement law. Classical isosteres have
the same valence electrons:

Group Replaced Bioisosteric Replacement(s)

-OH -SH, -NH2, -CH3, -F (metabolic blocker)

-COOH (carboxylic acid) -SO3H, -PO3H2, -tetrazole, -acylsulfonamide, -hydroxamic acid

-C=O (carbonyl) -C=S, -C=NH, -C=CH2

-NH- (secondary amine) -O-, -S-, -CH2- (ring replacement)

Phenyl ring Pyridine, thiophene, furan, cyclopentadiene (ring bioisosteres)

-F, -Cl -CF3, -CN, -CCl3 (non-classical)

-CH3 (methyl) -Cl, -Br, -CF3, -C≡N

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 Non-Classical Bioisosteres
Functional groups or ring systems that mimic the spatial, electronic, or hydrogen bonding characteristics
of another group without being strictly isoelectronic.
• -COOH → Tetrazole: Tetrazole is a bioisostere of carboxylic acid — similar pKa (~4.5–5), similar
H-bonding, but more metabolically stable and lipophilic. Used extensively in angiotensin receptor
blockers (ARBs) — losartan, valsartan.
• Ester → Amide or reverse ester: Amides are more metabolically stable than esters; used to block
esterase hydrolysis.
• Benzene → Pyridine: Replacing benzene with pyridine introduces a basic nitrogen that can improve
solubility and direct P450 metabolism away from reactive positions.

Purposes of Bioisosteric Replacement

• Improve metabolic stability by blocking vulnerable sites
• Modulate pKa and solubility
• Alter lipophilicity (logP / logD)
• Improve membrane permeability
• Circumvent patents (patentability)
• Improve selectivity by exploiting subtle binding-site differences

5.3 Prodrug Design

A prodrug is a pharmacologically inactive or poorly active derivative of an active drug that is converted
to the active parent molecule in vivo by enzymatic or chemical transformation. Prodrug design is
employed when the active drug has:
• Poor oral bioavailability (low solubility, poor permeability)
• Rapid first-pass metabolism
• Local irritation or unpleasant taste
• Short duration of action

Types of Prodrugs
1. Ester prodrugs: The active carboxylic acid or alcohol is masked as an ester, hydrolysed by
esterases after absorption. Example: Enalapril (ester prodrug of enalaprilat; ACE inhibitor).
2. Phosphate prodrugs: Improve aqueous solubility of poorly soluble drugs. Example: Fosfluconazole
(phosphate prodrug of fluconazole); fosphenytoin → phenytoin.
3. Amide/carbamate prodrugs: Slow hydrolysis; used for sustained release. Example: Bambuterol
(carbamate prodrug of terbutaline).
4. Bioprecursor prodrugs: The prodrug molecule itself undergoes metabolic activation. Example:
Cyclophosphamide (activated by CYP3A4 to phosphoramide mustard); levodopa (decarboxylated to
dopamine by DOPA decarboxylase in brain).
5. Soft drugs: Active drugs designed to undergo predictable metabolic deactivation to non-toxic
metabolites after exerting their effect; opposite concept to prodrugs.

5.4 Scaffold Hopping

Scaffold hopping (also called molecular scaffold transformation) refers to the process of identifying new
chemical scaffolds that retain the biological activity of the original lead but have a different core ring

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 system. It is used to:
• Circumvent patents covering the original scaffold
• Improve ADMET properties while maintaining potency
• Discover novel chemical matter with different intellectual property
Strategies:
• Ring opening/closing: A flexible chain equivalent of a ring system, or the cyclised version of a
flexible compound.
• Ring expansion/contraction: 5-membered rings ↔ 6-membered rings; changes geometry and
H-bond geometry.
• Heteroatom scanning: Replacing one heteroatom in a ring with another (e.g., S → O, O → NH)
while maintaining shape.
• Topology hopping: Using 3D similarity searches (USR, ROCS) to find compounds with similar
shape and electrostatics but different 2D structure.
Example: Imatinib (Gleevec) scaffold was hopped to produce nilotinib and dasatinib, which are active
against imatinib-resistant BCR-ABL mutants.

5.5 Fragment-Based Drug Design (FBDD) in Lead Modification

In FBDD, small fragment hits (MW 150–250 Da, often with IC50 0.1–10 mM) identified by NMR or
crystallography are grown, linked, or merged into larger, high-affinity leads. This is a form of lead
generation/modification applicable when existing leads lack novelty or have poor ligand efficiency.
• Fragment growing: Adding substituents to the fragment guided by crystal structure to fill additional
binding pockets.
• Fragment linking: Connecting two fragments that bind to adjacent sub-pockets with a linker; highly
potent combinations can result (additive or sometimes synergistic binding).
• Fragment merging: Combining overlapping fragments sharing a common binding mode into a single
molecule.
Ligand Efficiency (LE): LE = −∆G / number of heavy atoms = 1.37 × pIC50 / HAC. Fragments typically
have high LE (>0.3 kcal/mol/atom); as the fragment grows into a lead, maintaining LE is critical.

5.6 Lipinski's Rule of Five and Drug-likeness

Christopher Lipinski (Pfizer, 1997) observed that most orally absorbed drugs and clinical candidates
obey the following rule set, now known as the Rule of Five (Ro5):

Lipinski's Rule of Five (Alka L. Gupta, Medicinal Chemistry)

• MW ≤ 500 Da

• Hydrogen bond donors (NH + OH) ≤ 5

• Hydrogen bond acceptors (N + O) ≤ 10

• cLogP ≤ 5 (lipophilicity)

• Note: Natural products and biologics are exempt from the Ro5

Violations of two or more rules predict poor oral absorption/permeability. Lead modification aims to keep
the evolving compound within these boundaries or justify any violations with experimental data.

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 Additional Drug-likeness Criteria
• Veber's rules (GSK, 2002): For rodent oral bioavailability — rotatable bonds ≤ 10 AND (TPSA ≤ 140
Å2 or H-bond count ≤ 12).
• Pfizer 3/75 rule: Compounds with cLogP > 3 and TPSA < 75 Å2 show highest promiscuous toxicity
rates — avoid this 'dangerous space'.
• Beyond Rule of Five (bRo5): Macrocyclic drugs and PROTACs with MW 700–1200 Da that still
achieve oral exposure through conformational chameleonic behaviour.

5.7 Other Lead Modification Strategies

A. Rigidification / Conformational Restriction
Reducing the conformational flexibility of a lead by introducing rings or double bonds to lock the
molecule in its bioactive conformation. Benefits: improved potency (reduced entropic penalty on
binding), improved metabolic stability, and improved selectivity.
• Example: Introduction of a ring to connect two side chains; cyclisation of an amide bond; introduction
of an alkene to replace a single bond.

B. Methyl Group Scanning (Magic Methyl Effect)

Introduction of a methyl group at strategic positions can dramatically improve potency (by filling a
hydrophobic pocket), metabolic stability (by blocking P450 hydroxylation), and sometimes selectivity.
The 'magic methyl' effect has been documented in many drug series.

C. Fluorine Incorporation
Fluorine is the most electronegative element. Its introduction into a lead can:
• Block metabolic oxidation (metabolic blocker) — CYP-mediated hydroxylation of aromatic rings
• Increase membrane permeability (due to increased lipophilicity in some positions)
• Improve binding affinity through electrostatic interactions and the 'fluorine gauche effect'
• Modulate pKa of adjacent amino groups
~20% of all approved drugs contain at least one fluorine atom. Examples: fluoxetine, ciprofloxacin,
atorvastatin, efavirenz.

D. Stereochemical Optimisation
Biological receptors are chiral; they often interact with only one enantiomer (the eutomer) productively.
The other enantiomer (the distomer) may be inactive, have a different mechanism, or even produce
adverse effects.
• Example: S-ibuprofen (eutomer) vs. R-ibuprofen; L-DOPA vs. D-DOPA; (S)-ketamine (anaesthetic)
vs. (R)-ketamine (greater psychotomimetic effects).
• Chiral switch: Marketing the pure eutomer of a racemate as a new drug (e.g., esomeprazole from
omeprazole; escitalopram from citalopram).

E. Peptidomimetics
For leads derived from peptides or protein segments, peptidomimetics replace the peptide backbone
with non-hydrolysable mimics to improve stability and bioavailability. Strategies include N-methylation,
retro-inverso peptides, azapeptides, β-peptides, and non-peptidic scaffolds that mimic the
pharmacophore.

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 UNIT 6 — IMPORTANT DEFINITIONS AT A GLANCE

Drug Target: A biomolecule (protein, nucleic acid, lipid) whose modulation by a drug produces a
desired therapeutic effect.

Hit Compound: A compound identified in primary HTS that shows confirmed, reproducible activity
against the target, but not yet extensively characterised.

Lead Compound: A chemically tractable, active compound with preliminary SAR data and acceptable
physicochemical properties, designated for iterative optimisation.

Development Candidate (DC): A fully optimised lead meeting all predefined in vitro and in vivo criteria
for advancement into formal preclinical and clinical development.

IC■■: Inhibitory Concentration 50% — concentration of a compound that inhibits 50% of the target
activity under defined assay conditions.

EC■■: Effective Concentration 50% — concentration producing 50% of maximum pharmacological

effect in a cell-based or functional assay.

K_i: Inhibition constant — thermodynamic measure of binding affinity of an inhibitor for its target; lower
K_i = tighter binding.

SAR: Structure-Activity Relationship — systematic correlation between structural features of

compounds and their biological activities.

QSAR: Quantitative SAR — mathematical/statistical models that quantitatively relate structural

descriptors to biological activity.

Pharmacophore: Minimum set of structural features (H-bond donor/acceptor, hydrophobic centre,

charged groups) responsible for optimal interactions with the target.

Bioisostere: Atom, ion, or group of atoms having similar size, shape, and electronic configuration to
another, producing comparable biological activity when substituted.

Prodrug: Pharmacologically inactive derivative of an active drug; converted to the active form in vivo by
enzymatic/chemical transformation.

ADMET: Absorption, Distribution, Metabolism, Excretion, Toxicity — the key pharmacokinetic and
safety parameters of a drug candidate.

Ligand Efficiency (LE): Binding energy per heavy atom (HAC); LE = −∆G / HAC; used to assess
quality of fragment and lead compounds.

Scaffold Hopping: Identification of structurally distinct chemical scaffolds that retain the biological
activity of a known lead compound.

Lipophilicity (logP/logD): Measure of partitioning between octanol and water; influences absorption,
distribution, and metabolism.

TPSA: Topological Polar Surface Area — sum of van der Waals surface areas of polar atoms;
correlates inversely with passive membrane permeability.

IND: Investigational New Drug — regulatory filing made before starting human clinical trials.

NDA / MAA: New Drug Application (USA) / Marketing Authorisation Application (EU) — regulatory
submission seeking approval to market a drug.

Eutomer: The enantiomer of a chiral drug with higher affinity/activity at the therapeutic target.

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 Distomer: The enantiomer with lower affinity/activity; may contribute to adverse effects.

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 UNIT 7 — REFERENCE BOOKS

1. Alka L. Gupta — Medicinal Chemistry S. Chand & Company, New Delhi.

Primary reference for [Link]. curriculum; covers drug design principles, lead compounds, bioisosterism, SAR, and
clinical development with Indian regulatory context.
2. V. Alagarsamy — Medicinal Chemistry Elsevier / Reed Elsevier India.
Comprehensive treatment of pharmacophore concepts, drug metabolism, receptor theory, and structure-based
drug design; widely used in PG pharmacy and chemistry courses.
3. Graham L. Patrick — An Introduction to Medicinal Chemistry Oxford University Press, 5th Ed.
Excellent introductory-to-advanced text; covers drug design, ADMET, prodrugs, bioisosteres with clear mechanistic
explanations.
4. Thomas L. Lemke, David A. Williams — Foye's Principles of Medicinal Chemistry Lippincott
Williams & Wilkins, 8th Ed.
Standard comprehensive reference for advanced medicinal chemistry; detailed SAR of all drug classes.
5. Erhardt & Böhm (Eds.) — The Practice of Medicinal Chemistry Academic Press / Elsevier, 4th Ed.
Industry-focused; covers drug optimisation, ADMET, intellectual property, and case studies from pharma
companies.
6. Hugo Kubinyi — QSAR: Hansch Analysis and Related Approaches Wiley-VCH.
Authoritative reference for QSAR methods.
7. A. Burger (Ed.) — Burger's Medicinal Chemistry and Drug Discovery Wiley, 6th Ed. (6 volumes)
Encyclopaedic reference covering all aspects of medicinal chemistry and drug discovery.

These notes are prepared for academic purposes for [Link]. Chemistry students at Kalyan PG College, Bhilai.
Content is based on standard medicinal chemistry textbooks as cited above. For examination preparation, students
are advised to consult the primary textbooks for additional examples, mechanisms, and figures.

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