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Computer-aided drug design

• In the most basic sense, drug design involves the design of molecules
that are complementary in shape and charge to the biomolecular
target with which they interact and therefore will bind to it. Drug
design frequently but not necessarily relies on computer
modeling techniques. This type of modeling is sometimes referred to
as computer-aided drug design.
• computer-aided drug design (CADD) approaches are being used in the
pharmaceutical industry to accelerate the process, low costly
• The theoretical basis of CADD involves quantum mechanics and
molecular modeling studies like structure based drug design;
ligand-based drug design
Molecular Modeling
• Molecular modelling cover all methods, theoretical
and computational, used to model or mimic the
behavior of molecules.
• The most common computational methods are based on either molecular
or quantum mechanics.
• Both this approaches produce equation for total energy of the structure.
• molecular mechanics(classical m.): molecular mechanics, molecular
• quantum mechanics: ab initio methods, semiemprical methods, density
functional theory
Classical Methods
• Molecular Mechanics: Molecular mechanics programs
use equations based on classical physics to compute
force fields.
• Atoms treated as spheres, bonds as springs and electron
are ignored.
• Force field refers to calculation of the interaction and energies between different atoms
between bond stretching, angle bending, torsional angle and non-bonded interaction
• Classical empirical force field
1) AMBER(Assisted Model Building and energy Refinement)
2) CHRAM (Chemistry at Harvard Macromoleculer Mechanics)
3) CVFF(Consistent Valence Force Field)
• Molecular dynamics: is a molecular mechanics program designed to
mimic the movement of atoms within a molecule.
• Molecular dynamics can be carried out a molecule to generate
different conformation which on energy minimization, give a range
of stable conformation. Alternatively bonds can be rotated in a
stepwise process to generate different conformation.
• Molecular dynamics can also be used to find minimum energy
structures and conformational analysis.
Quantum Mechanics
• Quantum mechanics is based on arrangement of electrons of
molecule and interaction of those electron with electron and nuclei of
other molecule.
• The Quantum mechanics based on finding solution to Schrödinger
wave equation.
• Quantum Mechanics Method:
1. ab inito method
2. Semiemperical method
3. Density functional theory
Ab inito method
• Ab initio translated from Latin means from “first principles”.
• This refers to the fact that no experimental data is used and
computations are based on quantum mechanics.
• It derived directly from theoretical principle.
• Different Levels of Ab Initio Calculations:
1. Hartree-Fock (HF): It based on Central field approximation.
2. Density Functional Theory (DFT): different from other ab initio
methods because the wave function is not used to describe a molecule.
total energy is expressed in term of total electron density
Semi Empirical Method
• Semi-empirical quantum methods, represents a middle road between
the mostly results available from molecular mechanics and the high
computationally demanding quantitative results from ab initio
• Semi empirical methods use experimental data to parameterize
• Like the ab initio methods, a Hamiltonian and wave function are used.
• Less accurate than ab initio methods but also much faster.
Choice of Method
• Molecular mechanics useful for
- Energy minimization
- Identifying stable conformation
- Energy calculation for specific conformations
- Studying molecular motion
- Studying different conformation.

• Quantum mechanics method are suitable

- Molecular orbital energies
- Heat formation for specific conformation
- Dipole moment
- Bond dissociation energy
- Transition-state geometries and energies
Molecular mechanics energy minimization
• Molecular mechanics is an approach of energy minimization that find stable, low
energy conformation by changing the geometry of a structure.
• Type of algorithms:
1)Steepest Descent algorithm
2)Conjugate gradient algorithm
3)Newton –Raphson algorithm
• The selection of energy minimization algorithms depends on size of system and
current state of optimization.
When molecule having larger than 200 atoms then conjugate gradient algorithm.
When molecule having less than 200 atoms then newton-raphson algorithm.
When molecule having larger than 10Kcal/mol/A then Steepest Descent
Types of Computer-aided drug design
• Ligand based drug design /direct approach
• Structure based drug design/ indirect approach
Structure based drug design
• relies on knowledge of the three dimensional structure of the
biological target obtained through :
x-ray crystallography
NMR spectroscopy.
Homology modeling
• identification of new ligands for a given receptor by searching large
databases of 3D structures of small molecules to find those fitting the
binding pocket of the receptor this called docking
• Rigid body docking methods we consider only static geometric /
physiochemical complementarities between ligand and target and ignore
flexibility and induced-fit binding models.
• flexible docking methods are still needed for refinement and optimization
of poses obtained from an initial rigid docking procedure.

• Components of Docking:
- Search algorithm: to identify the the possible conformation
Systematic Search, stochastic Search
- Scoring function : to predict interaction energy
Force field, empirical based, knowledge based
Ligand based drug design
• relies on knowledge of other molecules that bind to the biological target of
• used to derive a pharmacophore model that defines the minimum
necessary structural characteristics a molecule must possess in order to
bind to the target
• two fundamental approaches of LBDD are
(1) selection of compounds based on chemical similarity to known actives
using some similarity measure
(2) the construction of a quantitative structure activity relationship (QSAR)
model that predicts biological activity from chemical structure.
• pharmacophore is an abstract description of
molecular features that are necessary for
Molecular recognition of a ligand by a
biological macromolecule
• Typical pharmacophore features include
hydrophobic centroids, aromatic rings,
hydrogen bond acceptors or donors, cations,
and anions. These pharmacophoric points may be located on the ligand itself
or may be projected points presumed to be located in the receptor.