Drug Discovery Thought to Pharmacy Self

Dr. Mahesh Chhabria
Dept. of Medicinal Chemistry

L. M. College of Pharmacy
Ahmedabad – 380 009

Drug Discovery
Discovery of New Chemical Entity (NCE) eliciting desired biological response

• Continuous and Challenging • Started in 2700 B.C.

Why ?
• •
To get better and novel drug. Cancer, AIDS, Viral infections, certain CVS disorders – till without proper remedies. • Overcome certain adverse effects of existing drugs. e.g. NSAIDs – GI irrtitation; H1receptor antagonists – sedation & anticholinergic effects

How ?
• Traditional (SAR) approach
– Introduced in 1900

• Rational approach
– Introduced in 1960

Traditional Approach
Analogue Approach • Natural Source

• Based on serendipity and intuition • Based on chemical structure of lead • Random screening of large number of
compounds • Unusual Chemistry

– Plant, animal, micro-organisms, marine

Traditional Approach
1. Homolog Approach 2. Molecular Fragmentation 3. Molecular Addition 4. Isosteric replacement

Outcome …..
• Traditional Approach – Time consuming,
complex, costly, less productive What is the need of time ? Efforts on cutting cost DD by reducing actual number of compounds to be synthesised and screened and still achieving better success rate “ Smarter Drug Design ”

Rational Approach
Mechanism based drug design

• Target site / diseased state – considered • No importance to chemical structure • Planned synthesis and screening • H-bonding, electro negativity values,

Potential energy, Anchoring sites, Size etc. are considered • New molecules

Drug Design
Research tool for novel drug discovery Efforts to develop new drugs on rational basis so as to decrease the trial and error factors and predict the biological activity before their synthesis

Drug Design (contd.)
Points to be considered – 1. Geometry of the receptor 2. Molecular structure of drug 3. Behavior of the drug in the biophase 4. Drug-receptor interaction 5. Changes in structure on binding 6. Resulting biological response

Drug Design (contd.)
Multidisciplinary Approach • Computer • Medicinal / Organic Chemistry • Molecular Pharmacology / Biophysics • Crystallography / Spectroscopy • Biopharmaceutics / Pharmacokinetics

Path of Drug Discovery
Target Identification (Data base) Lead Identification (Data base, MM) Lead Generation (Data base, Reaction files) Lead Modification (Data base, QSAR) Lead Optimisation (QSAR) Preclinical and Clinical trials

Lead Molecule

Other formalities


Drug Design (cont.)

• Molecular modeling • QSAR

Molecular Modeling
Describes the generation, manipulation and representation of three dimensional structures of molecules and associated physicochemical properties

MM Process
Define Problem (Data base) Build Molecules Visualization & Calculations Analyze Results

• Quantum Mechanics:
– Calculation of electronic properties implicated on both physical and chemical properties of molecule with their biological environment – Molecular mechanics is a method of calculating the potential energy of an isolated molecule or system of interfering molecules. – Molecular dynamics simulations can be used to describe many kinds of the events involved in drug-receptor interactions, including solvation and conformational changes required for initial complex formation

• Molecular Mechanics: • Molecular Dynamics:

Requirements for MM
• Hardware: • Software
– Complicated calculations – computer – work station – Digital, IBM, HewlettPackard, Silicon Graphics – As per requirements – Modules – PC based softwares are Available – Accelrys (Discover), Tripos (Sybyl), CCG (MOE)

Types of MM
1. Direct type of MM
 Receptor or structure based MM

1. Indirect type of MM
 Chemical structure based MM


Receptor based MM

Indirect type of MM

Advantages and Disadvantages of MM
• De novo drug design • Helps to understand the various

properties of the molecule. Fails when, • Multiple modes of actions. • Unexpected conformational changes and pharmacokinetic behavior of molecule.

Method to establish quantitative relationship between the descriptors and biological properties of the molecules

Why QSAR ?
• Prediction of the biological activity • Classification of compounds • Optimisation of biological activity • Lead Search • Reduction in use of animals • Minimise random synthesis • Economise new drug discovery

Various Methods of QSAR
• 1. Free Energy Models • •
– – 2. 3. – – – – – 4. 5. 6. Hansch Model – LFER Martin & Kubynie Model – Non LFER Free Wilson Mathematical model Other statistical Models Discriminant Analysis Principal Component Analysis Factor Analysis Cluster Analysis Combined Multivariate Analysis Pattern Recognition Topological Method Quantum Mechanical Methods

• • •

Hansch Model - Random walk


C Response


Extracellular Random walk Phase L L, St

Critical reaction site E L, E,St

Hansch Model
Principle B.A. ƒ ∆ L, ∆ E, ∆ St • Linear Form Log1/c = alogP + bσ + dEs + c


Requirements for QSAR
• Biological Activity Data
– Large range in observed activity (min. 5 compounds/ parameter) – Identical mode of action – Concentration in Molar units (g/kg – not suitable) – Activity data as function of concentration, i.e, ED50 , I50 , IC50 , LD50 , MIC, MBC etc.. – Activity data in % i.e. protein binding, metabolism to be transformed to “log”.

Requirements for QSAR
• Physico-chemical & structural
– Large range of parameter used – No significant intercorrelation between descriptors – About five derivatives per parameter – Homogenous distribution in the parameters used.

Physicochemical Parameters
Electronic Parameters
– Experimental Parameters • Ionisation Constant Pka, ∆ Pka • Sigma substituent constant
– – – – – – σ , σ -, σ +, σ *,


= log KR/log KH

Taft’s constant Inductive substituent constant Spectroscopic Chemical Shift IR, NMR Resonance Effect R Field Effect F Ionisation Potetial I

Electronic Parameters – Theoretical Quantum
1. Atomic Charge Densities 2. Atomic Net Charge 3. Super Deionisation 4. Energy of Molecular Orbital

Physicochemical Parameters
• Lipophilic Parameters
– – – Partition Coefficient log P, (logP)2 Pi-substituent coefficient π , π 2 Rm-Chromatographic parameter

– Elution time by HPLC log K’

capacity factor K’ = tr-t0/t0
– Solubility δ

Physicochemical Parameters
• Stearic Parameter
– – – Taft’s steric substituent constant Vanderval’s dimensions Vw, rv Molecular connectivity ƒ = Σ cij; Cij = 1/ δ i – Parachor [P]
[P] = VŸ¼ = MŸ ¼ /D


– – –

Charton’s steric constants Minimal Steric Difference (MSD) Sterimol parameters

Data generation and Analysis
• QSAR software • Regression analysis (simple and multiple)
– Multiple correlation coefficient – r , q – F- test – Standard error of estimate - s – – – – Coefficient of parameters Standard error T- test Inter correlation between parameter – Biological activity & physicochemical parameter value (data base or practical)

• Equation

Prediction of Biological Activity

Pharmacokinetics in Drug Discovery
The activity in vitro does not guarantee a sufficient in vivo effect ~ may be attributed to the PK behavior of drug molecule PK Processes Absorption, Distribution, Metabolism, Elimination Toxicity

What is Pharmacokinetics ? A Pharmacokinetic model describes the change in the amount of drug (“pharmaco”) in the body with time (“kinetic”)

Structural modification and PK
PK consequences expected as a result of structural modifications in drug molecule
1. 2. 3. 4. 5.
Absorption rate Volume of distribution Metabolism rate Affinity constant for binding to serum proteins Rate and type of elimination

• To estimate the influence of small

structural changes on PKs of a drug can be correlated with the change in physicochemical parameters. • Quantitative estimation of this correlation can be obtained by


QSPR (Quantitative Structure Pharmacokinetic

PK ƒ ∆ L, ∆ E, ∆ St
PK parameters
1. Absorption rate constant; Ka 2. Rate constants of metabolism; Km 3. Rate constant of elimination; Kel 4. Volume of distribution Vd 5. Degree of binding to Plasma proteins

Advantages of QSAR/QSPR
• Help to understand the forces underlying
the drug action without knowing the structure of receptor involved. • Help to understand factors involved in transport, metabolism and excretion of drugs. • It helps in predicting more potent drugs without synthesizing them. (reduce time and cost)

Disadvantages of QSAR/QSPR
• Insufficient number of compounds and
unsatisfactory biological data may lead to untrue conclusions • Intercorrelation between two parameters need to be eliminated. • Useful for refining a series and not for the de novo research. • Static and not a dynamic model (2D & not 3D) 3D-QSAR

Important books for Reference
• “Comprehensive Medicinal Chemistry”, Vol. 4, ed. • • • •
C. A. Ramsden, Pragmon Press. “Drug Design” Vol. 1, ed., E. J. Ariens, Academic Press, New York. “Berger’s Medicinal Chemistry and Drug Discovery”, Vol. 1, ed. M. E. Wolff, Willey interscience Publication “Quantitative Drug Design” by Y. C. Martin, Marcel Dekker Inc., New York. “Journal of Medicinal Chemistry”, ACS Publication

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