CADD and Molecular Modeling

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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

    i

    l

    e

    N

    DA

    http://images.google.com/imgres?imgurl=www.elements.nb.ca/theme/health/patty/sick.jpg&imgrefurl=http://www.elements.nb.ca/theme/health/theme.htm&h=128&w=75&prev=/images%3Fq%3Dsick%2Bclipart%26svnum%3D10%26hl%3Den%26lr%3D%26ie%3DUTF-8%26safe%3Doff
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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

    http://var/www/apps/conversion/tmp/scratch_1/C:%5CRASMOL%5CRASWIN32.exe%20-script%20H3design.rashttp://var/www/apps/conversion/tmp/scratch_1/.%5C%5Crw32b2a.exe%20-script%20H3design.rashttp://var/www/apps/conversion/tmp/scratch_1/.%5C%5Crw32b2a.exe%20-script%20H3design.rashttp://var/www/apps/conversion/tmp/scratch_1/.%5C%5Crw32b2a.exe%20-script%20H3design.rashttp://var/www/apps/conversion/tmp/scratch_1/C:%5CDocuments%5CPresentations%5CCurrent%5Censemble.rashttp://var/www/apps/conversion/tmp/scratch_1/.%5C%5Crw32b2a.exe%20-script%20protein.ras
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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