BIOCHEMICAL

APPROACHES FOR
DRUG DESIGN

SEMINAR BY:

T.SRAVYA
 Drug design
Drug designing is an
process of finding new
medications based on the
knowledge of the biological
target.
 TWO APPROACHES

1. RECEPTOR BASED
APPROACH

2. GENE BASED APPRAOCH

 Receptor Structure REQUIREMENT
Lead Compound and
derivatives with biological
REQUIREMENT
data
A Model Receptor Known Unknown

Analog Based
Drug Design
Structure Based
Drug Design
Homology Modeling
Receptor Mapping

Docking QSAR
Quantum
Molecular Dynamics PCA Mechanics for
Quantum
Simulations Alignment
Mechanical
(BRABO) ANN
Rigid Docking CoMFA
Simulated Annealing GA CoMSIA
FlexiDock
Quantum
Monte Carlo Mechanical
Simulations SINGLE MOLECULE Descriptors

SYBYL, INSIGHT II, CERIUS2, MOE, AMBER (CDAC), DOCK, AUTODOCK

 Receptor based
Drug Design

Structure based Ligand based

 What is Docking?

Docking attempts to find the “best” matching between two molecules

Docking of Ligand to the Active site of
Protein
3D Structure of the
Complex

Experimental
Information: The active
site can be identified
based on the position of
the ligand in the crystal
structures of the protein-
ligand complexes

If Active Site is not KNOWN?????

 Building Molecules at the
Binding Site

Identify the binding regions Evaluate their disposition in space

Search for molecules in the

library of ligands for similarity
 .

Put a compound in the approximate area

where binding occurs and evaluate the
following:
Do the molecules bind to each other?
If yes, how strong is the binding?
How does the molecule (or) the protein-
ligand complex look like. (understand the
intermolecular interactions)
Quantify the extent of binding.
 .

• Computationally predict the structures of

protein-ligand complexes from their
conformations and orientations.
• The orientation that maximizes the
interaction reveals the most accurate
structure of the complex.
• The first approximation is to allow the
substrate to do a random walk in the space
around the protein to find the lowest
energy.
 Ligand in Active Site Region

Ligand

.
 Examples of Docked
structures
HIV protease inhibitors COX2 inhibitors
Exact Receptor Structure is not
always known
• Receptor Mapping

The volume of the binding

cavity is felt from the ligands. This
receptor map is derived by looking
at the localized charges on the
active ligands and hence assigning
the active site.
 Receptor Map
Proposed for
Opiate Narcotics R3
(Morphine, Codeine, Heroin,
etc.)

R2 R1
7.5-8.5Å

Anionic site
6.5Å
Focus of charge
*
Cavity for part of piperidine ring

Flat surface for aromatic ring

 Homology modeling

Predicting the tertiary structure of an unknown

protein using a known 3D structure of a
homologous protein(s) (i.e. same family).
Assumption that structure is more conserved than
sequence
 How to construct homologous
model?
• Find homologous sequence
• Select the template sequence of
known
• structure
• Align the template and the target
structure
• Build the model
•And finally… Build the model .It is the
moment to use a MODELLER program
•In input: target, template sequence
and their
alignment
•In output: the 3D structure responding
of
the constraints
Quantative Structure-
Activity Relationships
 What is QSAR?
A QSAR is a mathematical
relationship between a biological
activity of a molecular system and its
geometric and chemical
characteristics.
QSAR attempts to find consistent
relationship between biological
activity and molecular properties, so
that these “rules” can be used to
evaluate the activity of new
 Introd
Why
Why QSAR?
QSAR?
QSAR and Drug Design
Compounds + biological activity

QSAR

New compounds with

improved biological activity
 Statistical Concept

Pi = k(d1, d2, d3,…. Dn)

• pi= biological
activity
• d1, d2 =
descriptors( cal
culated
structural
properties)
 QSAR MODELLING
APPROACHES
3D-QSAR
A.CoMFA
VARIABLE QSAR SELECTION APPROACHES
A.LINEAR MODEL
B.NON LINEAR
3D QSAR
 3D QSAR
Compound Number Biol. Activity Steric
Interactio
S001
1 1.07
2 0.09
3 0.66
 CoMFA 3D-QSAR

Problems:
The molecules must be optimally
aligned.
Flexibility of the molecules.
3D-QSAR of CYP450cam with
CoMFA

Maps of electrostatic fields:

BLUE - positive charges
RED - negative charges
Maps of steric fields:
GREEN - space filling areas
YELLOW - space
conflicting areas
 ACHIEVEMENTS

• Forecasting of biological
activity
•Selection of proper
substituents
•Drug receptor interactions
•Pharmacokinetic information
•Bioisosterism
GENE BASED
APPROACH

.
Gene-based Approach
√ Gene Therapy

Transfer of a therapeutic gene into the target

tissue and maintenance of the gene function
for an acceptable time

Pote
33
Gene-based Approach
√ Gene Therapy – Basic Steps

34
Gene-based Approach
√ Gene Therapy – Basic Steps

• Discover Genes
• Design Replacements
• Deliver to cell / body
• Ensure Incorporation
• Detect Function
• Ensure Stability
• Test Toxicity
• Test long-term effects
35
Gene-based Approach
√ Gene Therapy – Delivering Genes

Basic Methods
Method

Physical Methods 36
√ Delivering Genes – Cells

37
 .

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