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CADD and Molecular
Modeling : Importance inPharmaceutical Development
Dr. Sanjeev Kumar SinghDepartment of BioinformaticsAlagappa Universitye-mail- [email protected]
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Working at the Intersection
Structural Biology
Biochemistry
Medicinal Chemistry
Toicology
Pharmacology
Biophysical Chemistry
In!ormation Technology
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Structural Biology
"astest gro#ing
area o! $iology
Protein and nucleic
acid structure and
!unction
%o# proteins
control livingprocesses
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Medicinal Chemistry
&rganic Chemistry
Applied to disease
'ample: design
ne# en(ymeinhi$itor drugs
doxorubicin (anti-cancer)
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Pharmacology
Biochemistry o! %uman Disease
Di!!erent !rom Pharmacy: distri$utiono! pharmaceuticals) drug deliverysystems
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*e# Ideas "rom *ature
Natural ProductsChemistry
Chemical Ecology
During the next twodecades: the majoractivity in organismalbiology
Examles: enicillin!taxol (anti-cancer)
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Bio+Chem,in!ormatics
The collection) representation and organisation o!
chemical data to create chemical in!ormation) to #hich
theories can $e applied to create chemical kno#ledge-
Aim Toeamine ho# computational techni.ues can $e used
to assist in the design o! novel $ioactive compounds-
To give an idea o! ho# computational techni.ues can
similarly $e applied to other emerging areas such as Bio,
in!ormatics) Chemin!ormatics / Pharmain!ormatics-
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&vervie#
Drug discovery process
%o# do drugs #ork0
&vervie# o! Computer,Aided DrugDesign
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Pharmaceutical+AgrochemicalIndustry
Identi!ication o! novel compounds #ith use!ul andcommercially valua$le $iological properties-
vastly comple) multi,disciplinary task
many stages over etended periods o! time
1isk most novel compounds do not result in a drug-
those that do may cause unepected) long,termside,e!!ects"
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Why CADD20
Drug Discovery today are !acing a serious
challenge $ecause o! the increased cost and
enormous amount o! time taken to discover
a ne# drug) and also $ecause o! rigorouscompetition amongst di!!erent
pharmaceutical companies-
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Drug Discovery / Development
Identify disease
Isolate protein
involved in
disease (2-5 years)
Find a drug effective
against disease protein
(2-5 years)
Preclinical testing
(1-3 years)
Formulation
Human clinical trials
(2-10 years)
cale-up
F!" approval
(2-3 years)
i
l
e
I
N
D
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DA
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Drug Development Process
On average it takes 12 -15years and costs ~$500 -800million to bring a drug tomarket
develop
assay
lead
optimisation
lead
identification
clinical
trials
to market
10,000scompounds
1 drug
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Cont2
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Technology is impacting this process
Identify disease
Isolate protein
Find drug
Preclinical testing
GENOMICS, PROTEOMICS & BIOPHARM.
HIGH THROUGHPUT SCREENING
MOLECULAR MODELING
VIRTUAL SCREENING
COMBINATORIAL CHEMISTRY
IN VITRO & IN SILICO ADME MODELS
Potentially producing many more targets
and #personali$ed% targets
creening up to 100&000 compounds a
day for activity against a target protein
'sing a computer to
predict activity
apidly producing vast numers
of compounds
*omputer grap+ics , models +elp improve activity
issue and computer models egin to replace animal testing
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utomating t!e "## rocess
Gene sequence data
X-ray or
Homology
Screening
Library synthesis
%ed "!em&"ombic!em
'ibmaker(%
Designed libraries
Ligand binding data
PharmacophoreModel
Skelgen
Designed Templates
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Target
Identification
Target
Validation
Lead
IdentificationLead
Optimization
Target discovery Lead discovery
!ases o) "##
SAVING12 15 years, Costs: 500 - 800 million
US $
VHTSVHTS
Similarity
analysis
Similarity
analysis
Database
filtering
Database
filtering
Computer ided
Drug Design!CDD"
de novo
design
de novo
design
diversity
selection
diversity
selection
#iop$ores#iop$ores
lignmentlignment
Combinatorial
libraries
Combinatorial
libraries
D%&TD%&T
'S('S(
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%o# Drugs Work
Substrate&nzyme
+
&nzyme)substrate
comple*
Lock)and)key model
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Methodologies and strategies o!CADD:
Structure $ased drug design 3SBDD4 5DI1'CTD'SI6*7
"ollo#ed #hen the spatial structure o! thetarget is kno#n-
8igand $ased drug design 38BDD4 5I*DI1'CTD'SI6*7
"ollo#ed #hen the structure o! the target isunkno#n-
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Computer,Aided Drug Design
9,D target structure unkno#n 38BDD4 1andom screening i! no actives are kno#n
Similarity searching
Pharmacophore mapping
SA1 3;D / 9D4 etc-
Com$inatorial li$rary design etc-
Structure,$ased drug design 3SBDD4 Molecular Docking
De novo design
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#n Pharmacohore$
Pharmacoporic Studies on AC'inhi$itors
Pharmacological Studies on %I
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What is Pharmacophore20
Pharmacohore model
%et o& oints in sace de&ining the binding o& ligandswith target"
'ey &actors in develoing such a model are the
determination o& &unctional grous essential &orbinding! their corresondence &rom one ligand toanother! and the common satial arrangement o& thesegrous when bound to the recetor
The pharmacophore model o! %I< protease-
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Pharmacophore2--0 a molecular &ramewor that carries (horos) the
essential &eatures resonsible &or a drug*s(harmacon) biological activity+ Paul 'rlich) [email protected]
a set o& structural &eatures in a molecule that isrecogni,ed at a recetor site and is resonsible &orthat molecule*s activity+ Peter 6und) =?
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Basic "eatures
A set o! !eatures common to a series o! activemolecules
What are the !eatures20 %BD
%BA ve /,ve charged groups and %ydropho$ic regions
"unctional groups or molecules #ith similarphysical and chemical properties
Bioisosteres , su$stituents or groups thathave chemical or physical similarities and#hich produce $roadly similar $iologicalproperties
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Pharmacophore model
%et o& oints in sace de&ining the binding o& ligandswith target"
'ey &actors in develoing such a model are thedetermination o& &unctional grous essential &orbinding! their corresondence &rom one ligand toanother! and the common satial arrangement o& thesegrous when bound to the recetor"
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AC'
Angiotensionconverting en(yme
Converts
angiotensinI toangiotension II
Inhi$its $radykinin3vasodi
