IN SILICO DRUG DESIGN TECHNIQUES 1...(QSAR) •Comparative molecular field analysis (CoMFA)...
Transcript of IN SILICO DRUG DESIGN TECHNIQUES 1...(QSAR) •Comparative molecular field analysis (CoMFA)...
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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.
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• IN SILICO DRUG DESIGN : means rational
design by which drugs are designed /
discovered by using computational methods.
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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.
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• 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
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• 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.
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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
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• 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.
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• 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.
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• 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 :
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• 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.
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• 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.
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• 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.
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• 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.
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• 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.
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• 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.
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TARGET SELECTION LIGAND SELECTION
TARGET PREPARATION LIGAND PREPARATION
DOCKING
EVALUATING DOCKING RESULT
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• 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.
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• 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.
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• 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.
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• 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.
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• Structural Bioinformatics, Edited by Philip E.
Bourne and Helge Weissig.(pdf)
• Wikipedia
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