Medicinal chemists today are facing a

serious challenge because of the

increased cost and enormous amount of
time taken to discover a new drug, and
also because of fierce competition
amongst different drug companies
 Drug Discovery & Development
Identify disease Drug Design
- Molecular Modeling
- Virtual Screening
Find a drug effective
against disease protein
Isolate protein (2-5 years)
involved in Scale-up
disease (2-5 years)

Preclinical testing
(1-3 years) Human clinical trials

D
IN
(2-10 years)

le
Fi
Formulation

A
ND
le
Fi
FDA approval
(2-3 years)
 Technology is impacting this process
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
 History of Drug Discovery….
•1909 - First rational drug design.
•Goal: safer syphilis treatment than Atoxyl.
•Paul Erhlich and Sacachiro Hata wanted to maximize toxicity to
pathogen and minimize toxicity to human (therapeutic index).
•They found Salvarsan (which was replaced by penicillin in the
1940’s)
HO O
ClH.H 2N NH2 .HCl
As
O
HO As As OH
H 2N Na+
Atoxyl
Salvarsan
•1960 - First successful attempt to relate chemical structure to
biological action quantitatively (QSAR = Quantitative structure-
activity relationships). Hansch and Fujita
 History of Drug Discovery
• Mid to late 20th century
- understand disease states, biological structures, processes,
drug transport, distribution, metabolism.
Medicinal chemists use this knowledge to modify chemical
structure to influence a drug’s activity, stability, etc.

• procaine = local anaesthetic; Procainamide = antirhythmic

O O
H 2N OCH2CH2N(C2H5 )2 H 2N NHCH2CH 2N(C 2H5) 2

Procaine Procainamide
Evolutionary drug designing
Ancient times: Natural products with
biological activities used as drugs.
Chemical Era: Synthetic organic
compounds
Rationalizing design process: SAR &
Computational Chemistry based Drugs
Biochemical era: To elucidate biochemical
pathways and macromolecular structures
as target as well as drug.
 Molecular Modeling
NMR and X-ray QSAR/3D QSAR
structure determination Structure-based drug design
Rational drug design

Model construction
Molecular mechanics
QM, MM methods Homology modeling
Conformational searches
Molecular dynamics

Combinatorial chemistry Bioinformatics

Chemical similarity Chemoinformatics
Chemical diversity
What is Molecular Modeling?
Molecular Graphics: Visual representation
of molecules & their properties.

! Computational Chemistry: Simulation of

atomic/molecular properties of compound
through computer solvable equations.

SS ( b’-b’0)[ V1cosf] b’f SS (q-q0) [V1cosf]

! Statistical Modeling: D-R, QSAR/3-D QSAR Molecular data

! Information Management: Organizational databases retrieval
/search & processing of properties of 1000… of compounds.

MM = Computation + Visualization + Statistical modeling

+ Molecular Data Management
COMPUTATIONAL TOOLS:
QM/MM

(A) MOLECULAR MECHANICS (MM)

(B) QUANTUM MECHANICS (QM)

COMPUTATIONAL TOOLS
Quantum Mechanics (QM)
Ab-initio and semi-empirical methods
Considers electronic effect & electronic
structure of the molecule
Calculates charge distribution and orbital
energies
Can simulate bond breaking and formation
Upper atom limit of about 100-120 atoms
 COMPUTATIONAL TOOLS
Molecular Mechanics (MM)
! Totally empirical technique applicable to
both small and macromolecular systems
! a molecule is described as a series of
charged points (atoms) linked by springs
(bonds)
! The potential energy of molecule is
described by a mathematical function called
a FORCE FIELD
Sir Isaac Newton Erwin Schrödinger
(1642 - 1727) (1887 - 1961)

F = ma ĤY = eY
 Quantitative Structure Activity
Relationships (QSAR)
QSARs are the mathematical relationships linking chemical
structures with biological activity using physicochemical or any other
derived property as an interface.

Biological Activity = f (Physico-chemical properties)

Mathematical Methods used in QSAR includes various regression
and pattern recognition techniques.

Physicochemical or any other property used for generating QSARs is

termed as Descriptors and treated as independent variable.

Biological property is treated as dependent variable.

 QSAR and Drug Design

Compounds + biological activity

QSAR

New compounds with

improved biological activity
Types of QSARs
Two Dimensional QSAR

- Classical Hansh Analysis

- Two dimensional molecular properties

Three Dimensional QSAR

- Three dimensional molecular properties

- Molecular Field Analysis

- Molecular Shape Analysis

- Distance Geometry

- Receptor Surface Analysis

 QSAR ASSUMPTIONS

The Effect is produced by model compound and not it’s

metabolites.

The proposed conformation is the bioactive one.

The binding site is same for all modeled compounds.

The Bioactivity explain the direct interaction of molecule and

target.

Pharmacokinetics aspects, solvent effects, diffusion, transport

are not under consideration.
 QSAR Generation Process
1. Selection of training set
2. Enter biological activity data
3. Generate conformations
4. Calculate descriptors
5. Selection of statistical method
6. Generate a QSAR equation
7. Validation of QSAR equation
8. Predict for Unknown
 Descriptors
1. Structural descriptors
2. Electronic descriptors
3. Quantum Mech. descriptors
4. Thermodynamic descriptors
5. Shape descriptors
6. Spatial descriptors
7. Conformational descriptors
8. Receptor descriptors
 PHARMACOPHORE APPROCH
Pharmacophore:
The Spatial orientation of various functional groups or
features in 3D necessary to show biological activity.

Types of Pharmacophore Models

Distance Geometry based Qualitative Common

Feature Hypothesis.

Quantitative Predictive Pharmacophores from a

training set with known biological activities.
Pharmacophore-based Drug Design
•Examine features of inactive small molecules (ligands) and the
features of active small molecules.
•Generate a hypothesis about what chemical groups on the ligand
are necessary for biological function; what chemical groups
suppress biological function.
•Generate new ligands which have the same necessary chemical
groups in the same 3D locations. (“Mimic” the active groups)

Advantage: Don’t need to know the biological target structure

 Pharmacophore Features
HB Acceptor & HB Donor
Hydrophobic
Hydrophobic aliphatic
Hydrophobic aromatic
Positive charge/Pos. Ionizable
Negative charge/Neg. Ionizable
Ring Aromatic

Each feature consists of four parts:

1. Chemical function
2. Location and orientation in 3D space
3. Tolerance in location
4. Weight
Receptor-based Drug Design
•Examine the 3D structure of the biological target (an X-ray/ NMR
structure.
•Hopefully one where the target is complexed with a small molecule
ligand (Co-crystallized)
•Look for specific chemical groups that could be part of an attractive
interaction between the target protein and the ligand.
•Design a new ligands that will have sites of complementary
interactions with the biological target.

Advantage: Visualization allows

direct design of molecules
 Docking Process
Put a compound in the approximate area where
binding occurs

Docking algorithm encodes orientation of

compound and conformations.

Optimize binding to protein

– Minimize energy
– Hydrogen bonding
– Hydrophobic interactions

Scoring
“Docking” compounds into
proteins computationally
De Novo Drug Design
Build compounds that are complementary to a target binding site
on a protein via “random” combination of small molecular
fragments to make complete molecule with better binding profile.
• Can pursue both receptor and pharmacophore-based approaches
independently
• If the binding mode of the ligand and target is known,
information from each approach can be used to help the other

Ideally, identify a structural model that explains the biological

activities of the known small molecules on the basis of their
interactions with the 3D structure of the target protein.
 Cheminformatics - Data Management

Need to be able to store chemical structure and

biological data for millions of data points
– Computational representation of 2D structure

Need to be able to organize thousands of active

compounds into meaningful groups
– Group similar structures together and relate to activity

Need to learn as much information as possible from the

data (data mining)
– Apply statistical methods to the structures and related
information
VIRTUAL SCREENING PROTOCOL

Objective - To search chemical compounds similar to active structure.

Essential components of protocol are as follows

• Substructure Hypothesis
• Pharmacophore Hypothesis
• Shape Similarity Hypothesis
• Electronic Similarity Hypothesis

- VIRTUAL SCREENING

Library of ~ 2 lac compounds was screened

• Initially 800 compounds were short listed applying above filters.

• Further 30 compounds were selected by applying diversity & similarity
analysis.

- Compounds have been in vitro screened and found various new scaffolds
 Virtual Screening
Build a computational model of activity for a particular
target
Use model to score compounds from “virtual” or real
libraries
Use scores to decide which to make and pass through a
real screen
We may want to virtual screen

- All of a company’s in-house compounds, to see which to

screen first
- A compound collection that could be purchased
- A potential chemistry library, to see if it is worth making,
and if so which to make
Virtual Screening
 In-Silico ADMET Models
Computational methods can predict compound properties
important to ADMET

– Solubility
– Permeability
– Absorption
– Cytochrome p450 metabolism
– Toxicity

Estimates can be made for millions of compounds, helping

reduce “attrition” – the failure rate of compounds in late
stage