IN SILICO : is a term that means “computer aided”.

DRUG DESIGN : Referred to as rational drug design

or simply rational design is the inventive process

of finding new medications based on theof finding new medications based on the

knowledge of a biological targets.

RATIONAL DESIGN : is the strategy of creating new

molecules with a certain functionality, based

upon the ability to predict how the molecule's

structure will affect its behavior through physical

models.

• IN SILICO DRUG DESIGN : means rational

design by which drugs are designed /

discovered by using computational methods.

Two types

• Structure based drug designing

• Ligand based drug designing

• Structure based drug designing :Receptor• Structure based drug designing :Receptor

known, don’t know ligands.

• Ligand based drug designing : don’t know

receptor, known ligands.

• Homology modeling

• Molecular docking (Interaction networks)

• Quantitative structure activity relationship

(QSAR)(QSAR)

• Comparative molecular field analysis (CoMFA)

• Comparative molecular similarity indices

analysis (CoMSIA)

• 3D pharmacophore mapping

• Homology modeling is used to predict

the 3D-structure of a unknown protein

based on the known structure of a

similar protein.similar protein.

• The known structure is called the

template.

• The unknown structure is called the

target.

Homology modeling of the target structure can be done in 7 steps

• Template recognition and initial alignment

• Alignment correction• Alignment correction

• Backbone generation

• Loop modeling

• Side-chain modeling

• Model optimization

• Model validation

• In this step we compare the sequence of theunknown structure with all the knownstructures stored in the Protein Data Bank(PDB).

• The search can be performed using simplesequence alignment program such asBLAST(Basic Local Alignment Search Tool) andFASTA as the percentage identity between thetarget sequence and a possible templates.

• In practice the target-sequence is sent to a

BLAST server, which searches the PDB to

obtain a list of possible templates and their

alignments.alignments.

• Subsequently the best hit has to be chosen.

• Sometimes it may be difficult to align two

sequences in a region where the percentage

sequence identity is very low. One can then

use other sequences from homologoususe other sequences from homologous

proteins to find a solution.

• Example :

• Backbone generation : When the alignment iscorrect, the backbone of the target can becreated.

• The coordinates of the template-backbone• The coordinates of the template-backboneare copied to the target.

• Loop modeling : In the majority of cases, thealignment between target and templatesequence contains gaps.

• These gaps are molded by this method.

• Side-chain modeling : in this method addside-chains to the backbone of the target.

• Model optimization : Energy minimizationprocedure on the entire model, by adjustingprocedure on the entire model, by adjustingthe relative position of atom so that overallconformation of the molecule has the lowestpossible energy potential.

• The goal is to relieve steric collision withoutaltering the overall structure.

• Every model contains errors.

• The model should be checked for bumps and

if the bond angles, torsion angles and bond

lengths are within normal ranges.lengths are within normal ranges.

• Quantitative structure-activity

relationships (QSAR) methods are based

on the assumption that the structure of a

molecule (geometric, steric andmolecule (geometric, steric and

electronic parameter ) must contain the

features responsible for its physical ,

chemical and biological properties.

• Docking is an attempt to find the bestmatching between two molecules.

• Docking is a method which predicts thepreferred orientation of one Ligand whenbound in an active side to form a stablebound in an active side to form a stablecomplex.

• Molecular docking is a method to predictsthe preferred orientation of one molecule toa second when bound to form a stablecomplex with overall minimum energy.

• Molecular docking denotes Ligand

binding to its receptor or target protein.

• Molecular docking is used to recognize

and optimize drug candidates byand optimize drug candidates by

examining and modeling molecular

interactions between Ligand and target

macromolecules.

TARGET SELECTION LIGAND SELECTION

TARGET PREPARATION LIGAND PREPARATION

DOCKING

EVALUATING DOCKING RESULT

• There are several molecular docking tools

available that includes ArgusDock, DOCK,

FRED, eHITS, AutoDock and FTDock.

• Also used to generate multiple Ligand• Also used to generate multiple Ligand

conformations and orientations.

• Comparative molecular field analysis (CoMFA)

is a constructive novel technique to explain

structure activity relationship.

• It is a well-known 3D QSAR method .• It is a well-known 3D QSAR method .

• The aim of COMFA is to deliver a correlation

between the biological activity of set of

molecules and there 3D shapes, electrostatic

and hydrogen bonding.

• CoMSIA is recognized as one of the new 3D QSAR

approaches.

• It is generally used in the drug discovery process

to locate the common characteristics, essentialto locate the common characteristics, essential

for the proper biological receptor binding.

• This method deals with the steric and

electrostatic characteristics, hydrogen bond

acceptors, hydrogen bond donor and

hydrophobic fields.

• The 3D pharmacophore search is an

imperative, vigorous and simple method to

quickly recognize lead compounds

alongside a preferred target.

• A pharmacophore is defined as the specific• A pharmacophore is defined as the specific

3D arrangement of functional groups within

a molecular framework that are

indispensable to attach to an active site of

an enzyme or bind to a macromolecule.

• Structural Bioinformatics, Edited by Philip E.

Bourne and Helge Weissig.(pdf)

• Wikipedia