Lecture 10 pharmacophore modeling and sar paradox

pharmacophore modeling and sar paradox

1. Lecture10-PharmacophoreModelingandSARparadox
BTT-516–Drug Designing and Development

2. Apharmacophoreisaspecific3Darrangementoffunctionalgroupswithina
molecularframeworkthatarenecessarytobindtoamacromoleculeand/oran
enzymeactivesite
Theidentificationofpharmacophoreisimportantstepinunderstandingthe
interactionsbetweenareceptorandaligand
Pharmacophore

3. Pharmacophoreapproachesaresuccessfulsubfieldsofcomputer-aideddrug
design(CADD)whichhavebecomeoneofthemajortoolsinhitidentification,
leadoptimization,andrationaldesignofnoveldrugs.
Apharmacophoremodelistheensembleofcommonstericandelectronic
featuresthatarenecessarytoensuretheoptimalmolecularinteractionswitha
specificbiologicaltargetandtotrigger(orblock)itsbiologicalresponse.
Itcanbeusedtorepresentandcharacterizemoleculesonschematic2Dor3D
levelbyidentifyingtheessentialpropertiesofmolecularrecognition.Every
typeofatomorgroupinacompoundcanbereducedtoapharmacophore
feature(orpharmacophorefingerprints).Thesemolecularpatternswouldbe
labeledbyseveralchemicalproperties,suchashydrogenbonddonorsor
acceptors,aromatic,cationic,etc,whichcanbeusedtoanalyzethesimilarity
amongalibraryofsmallmoleculesandidentifythekeycontributingfeatures
tothebiologicalfunction.
PharmacophoreModeling

5. Ligand-based pharmacophoremodeling
Intheabsenceofthemacromoleculartargetstructure,ligand-basedpharmacophore
modelingisanessentialstrategyfordrugdiscovery.
Inthismethod,thecommonchemicalcharacteristicsfrom3Dstructuresofmultiple
knownligandsareextractedthroughligandalignment,whichwouldrepresentthe
essentialinteractionsbetweenligandandpotentialmacromoleculartarget.
Structure-based pharmacophoremodeling
Thestructure-basedpharmacophoremodelinggenerateschemicalfeaturesoftheactive
siteandthestericalrelationshipsfrom3Dstructureofmacromoleculartargetor
macromolecule-ligandcomplex.Itprobesthepossibleinteractionsitesbetweenthe
macromoleculartargetandtheligands.

6. Pharmacophoremodelingismostoftenappliedtovirtualscreeninginordertoidentify
moleculestriggeringthedesiredbiologicaleffect.
Forthispurpose,researcherscreateapharmacophoremodel(query)thatmostlikely
encodesthecorrect3Dorganizationoftherequiredinteractionpattern.
Purpose of pharmacophoremodeling
Why pharmacophoreis important?
Pharmacophoreistheessentialtounderstandtheinteractionbetweenthereceptorand
ligand.
Itisimportantfeaturetodesignnewdrugfortreatmentoftheintendeddisease.
Pharmacophoredefinedastheessentialgeometricarrangementofatomsorfunctional
groupsnecessarytoproduceagivenbiologicalresponse.

8. QingX,LeeXY,DeRaeymaeckerJ,TameJR,ZhangKY,DeMaeyerM,VoetA.
Pharmacophoremodeling:advances,limitations,andcurrentutilityindrugdiscovery.
JournalofReceptor,LigandandChannelResearch.2014;7:81-92.

9. SAR paradox and concept of force field
Thestructure–activity relationship(SAR) is the relationship between the chemical
structure of a molecule and its biological activity.
Structure-ActivityRelationship(SAR)isanapproachdesignedtofindrelationships
betweenchemicalstructure(orstructural-relatedproperties)andbiologicalactivity(or
targetproperty)ofstudiedcompounds.

10. Thebasicassumptionforallmoleculebasedhypothesesisthatsimilarmoleculeshave
similaractivities.ThisprincipleisalsocalledStructure-ActivityRelationship(SAR).
Theunderlyingproblemisthereforehowtodefineasmalldifferenceonamolecular
level,sinceeachkindofactivities
Examples:Reactionability,Biotransformationability,Solubility,targetactivity,andso
on,mightdependonanotherdifference.Agoodexamplewasgiveninthebioisosterism
reviewofPatanie/LaVoie.
Ingeneral,oneismoreinterestedinfindingstrongtrends.Createdhypothesesusually
relyonafinitenumberofchemicaldata.Thus,theinductionprincipleshouldbe
respectedtoavoidoverfittedhypothesesandderivingoverfittedanduseless
interpretationsonstructural/moleculardata.
TheSARparadoxreferstothefactthatitisnotthecasethatallsimilarmoleculeshave
similaractivities.

15. Thank you
Er. Rajan Rolta
Faculty of Applied Sciences and Biotechnology
Shoolini University,
Village Bhajol, Solan (H.P)
[phone] (Mob No.)
[email protected]