This document discusses in silico drug design. It begins by defining drugs and the drug design process. Drug molecules should be small, complementary in shape to the target, and oppositely charged. In silico drug design uses computer simulations to identify drug target molecules. There are ligand-based and structure-based approaches. Key steps are selecting a disease and target, target validation, selecting ligands, applying scoring functions, lead optimization, and preclinical/clinical development. The goal is to eliminate compounds that may cause side effects or drug interactions. In silico methods help integrate new technologies with traditional medicinal chemistry experience to discover safe and effective drug leads.

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PRESENATATION ON
INSILLICO DRUG
DESIGN

2. WHAT ARE DRUGS ?
 A chemical substance that affects the processes of the
mind or body which is used in
 Diagnosis
 Treatment
 Prevention of disease or other abnormal condition.
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4.  Drug Designing
 Drug designing, is the inventive process of finding
new medications based on the knowledge of a
biological target.
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5.  Drug designing…..
 Selected/designed molecule
should be:
 Organic small molecule.
 Complementary in shape to
the target.
 Oppositely charge to the
bio-molecular target .
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6.  Drug designing…..
 This molecule will:
 interact with target
 bind to the target
 activates or inhibits the function of a biomolecule
such as a protein
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7.  IN SILICO DRUG DESIGNING
 InSilico is an expression used to mean “performed
on computer or via computer simulation.”
 InSilico drug designing is defined as the
identification of the drug target molecule by
employing bioinformatics tools .
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9.  Ligand based drug design
 Ligand-based drug design relies
on knowledge of other
molecules that bind to the
biological target of interest
 Used to derive a
pharmacophore
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10.  Structure based drug
design
 Structure-based drug
design relies on
knowledge of the three
dimensional structure of
the biological target
obtained through methods
 such as
 x-ray crystallography
 NMR spectroscopy.
 homology modeling
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11.  Structure based drug design…..
 Using the structure of the biological target, drugs
that are predicted to bind with to the target may be
designed using
 interactive graphics
 the intuition of a medicinal
chemist.
 automated computational
procedures
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12. Basic Steps In In Silico Drug Designing
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13.  Selection of disease
 Determine the biochemical basis of the disease
process.
 Know the exact step(s) in the pathway that are
altered in the diseased state.
 Knowledge about the regulation of the pathway is
also important. Finally, one would know the three-
dimensional structures of the molecules involved in
the process.
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14.  Target selection
 Biochemical pathways could become abnormal and
result in disease.
 Select a target at which to disrupt the biochemical
process.
Categories of targets
 Target for mechanistic drug design usually fall into
three category:
 enzymes
 receptors
 nucleic acids.
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15.  Target Validation:
 Perform the protein BLAST for all the genes/proteins
with respect to Homo sapiens.
 Select the least matching molecule in human and
again perform the BLAST.
 As the query sequence matched best , so we selected
our target molecule and its structure can be obtained
from RCSB(The Research Collaboration for Structural
Bioinformatics) PDB(Protein Data Bank).
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16.  Selection of ligands/drugs
 Also called as Lead Identification
 High throughput screening of natural product and
synthetic compound libraries is carried to screen out
lead compound.
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17.  Criteria to be fulfilled…..
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18. Scoring
Scoring functions Quantify the energy of protein/ligand
interactions such as:
Hydrogen bond
Electrostatics
 Hydrophobic
Lead Optimization
Refining the 3D structure of the lead compounds.
 Technique used is QSAR.
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19. Preclinical and Clinical Development
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20.  CONCLUSION
 In the selection of new drug candidates, many efforts
are focused on the early elimination of compounds
that might cause several side effects or interact with
other drugs. In silico techniques help in this regard
and they are going to become a central issue in any
rigid drug discovery process.
 In silico technology alone cannot guarantee the
identification of new, safe and effective lead
compound but more realistically future success
depend on the proper integration of new promising
technologies with the experience and strategies of
classical medicinal chemistry.
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22.  Introduction
 A hit is a compound which has the desired activity in
a compound screen and whose activity is confirmed
upon retesting.
 Lead compounds are chemical compounds that show
desired biological or pharmacological activity and
may initiate the development of a new clinically
relevant compound.
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23.  Process of hit identification:
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24.  Hit identification:
 For hit identification, some information about either
the target protein or an active compound is
necessary.
 In the case of a known structure of the protein, a
virtual screening of compound libraries leads to
virtual hits which will be synthesised and tested
afterwards or tested immediately.
 If the structure of the natural substrate is known, a
ligand based approach will be accomplished.
 The computer searches for similar compounds and
the resulting hits are checked for drug like
properties.
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25.  Hit Identification Assay Features
 Protein target can be membrane bound, difficult to
produce for standard biochemical assays, and
difficult to purify;
 Hit and lead compounds and focused libraries can be
screened against protein target within physiological
environment;
 Compound cell permeability, specificity and
cytotoxicity are assessed in one process;
 Process can be upscaled to screen hundreds of
compounds in a few hours.
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26.  Assay development:
 Assay development one of the first steps in drug
development and toxicity testing is creating test
systems (assays) on which to evaluate the effects of
chemical compounds on cellular, molecular or
biochemical processes of interest.
 In the recombinant era the majority of assays in use
within the industry rely upon the creation of stable
mammalian cell lines over-expressing the target of
interest, or
 Upon the over-expression and purification of
recombinant protein to establish so-called
biochemical assays.
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27. Cont..
 Cell-based assays have been applied to target classes
such as membrane receptors, ion channels and
nuclear receptors.
 In contrast, biochemical assays, which have been
applied to both receptor and enzyme targets, often
simply measure the affinity of the test compound for
the target protein.
 The choice of assay format is dependent upon the
biology of the drug target protein, the equipment
infrastructure in the host laboratory, the experience
of the scientists in that laboratory, whether an
inhibitor or activator molecule is receive and the
scale of the compound screen.
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28. Cont…
 For example compound screening assays at GPCRs
have been configured to measure the binding affinity
of a radio- or fluorescently labelled ligand to the
receptor,
 To measure guanine nucleotide exchange at the level
of the G protein,
 To measure compound-mediated changes in one of a
number of second messenger metabolites including
calcium, cAMP or inositiol phosphates.
 Hit Identification Assay Applications
 Target identification or validation for hit phenotypic
screening.
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