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; H1-
receptor antagonists – sedation &
anticholinergic effects
How ?

• Traditional (SAR) approach

– Introduced in 1900

• Rational approach
– Introduced in 1960
Traditional Approach
Analogue Approach
• Natural Source
– Plant, animal, micro-organisms, marine
• Based on serendipity and intuition
• Based on chemical structure of lead
• Random screening of large number of
compounds
• Unusual Chemistry
Traditional Approach

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

SAR
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)
Lead Molecule
Preclinical and
Clinical trials
Other formalities
DRUG
Drug Design (cont.)

TOOLS

• 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
Cont…
• Quantum Mechanics:
– Calculation of electronic properties implicated on both
physical and chemical properties of molecule with their
biological environment
• Molecular Mechanics:
– Molecular mechanics is a method of calculating the
potential energy of an isolated molecule or system of
interfering molecules.
• Molecular Dynamics:
– 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
Requirements for MM
• Hardware:
– Complicated calculations – computer –
work station – Digital, IBM, Hewlett-
Packard, Silicon Graphics
• Software
– 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

Docking
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.
QSAR

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

Kx

C AC
Response

Extracellular Random walk Critical reaction

Phase site

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

log1/C

P
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

discriptors
– 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 *,
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
Cont…

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
Rm=log[1/Rf-1)
– Elution time by HPLC log K’
capacity factor K’ = tr-t0/t0
– Solubility δ
Physicochemical Parameters
• Stearic Parameter
– Taft’s steric substituent constant Es
– 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
– Biological activity & physicochemical parameter value (data
base or practical)
• Regression analysis (simple and multiple)
– Multiple correlation coefficient – r , q
– F- test
– Standard error of estimate - s
• Equation
– Coefficient of parameters
– Standard error
– T- test
– Inter correlation between parameter
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
Pharmacokinetics

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. Absorption rate
2. Volume of distribution
3. Metabolism rate
4. Affinity constant for binding to serum proteins
5. 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 physico-
chemical parameters.
• Quantitative estimation of this correlation
can be obtained by

QSPR
QSPR (Quantitative Structure Pharmacokinetic
Relationship)

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
Thank You