Pharmacophore modeling

Pharmacophore and types of pharmacophore modeling

1. Pharmacophore Modeling

2. Ligand in catalytic pocket
Protein(Cysteine Protease)
Protein with Ligand

3. Pharmacophore identification
•Pharmer
•Pharmapper
•Pharmagist
•Boomer
•ZincPharmer

4. Pharmacophore
•Theoriginalconceptofthepharmacophorewas
developedbyPaulEhrlichduringthelate1800s.
•Thewordpharmacophorewascoinedmuchlater,by
Schuelerinhis1960bookChemobiodynamicsandDrug
Design,andwasdefinedas“amolecularframeworkthat
carries(phoros)theessentialfeaturesresponsiblefora
drug’s(pharmacon)biologicalactivity.”
•Thedefinitionofapharmacophorewasthereforeno
longerconcernedwith“chemicalgroups”but“patternsof
abstractfeatures.

5. Pharmacophore
•InternationalUnionofPureandAppliedChemistry“A
pharmacophoreistheensembleofstericandelectronic
featuresthatisnecessarytoensuretheoptimal
supramolecularinteractionswithaspecificbiological
targetandtotrigger(orblock)itsbiologicalresponse”
•Significance
•Pharmacophorescanbeusedtorepresentandidentifymolecules
ona2Dor3Dlevelbyschematically.
•Themostcommonapplicationofpharmacophoresisvirtual
screening,anddifferentstrategiesarepossibledependingonthe
priorknowledge
•ThepharmacophoreconceptisalsousefulforADME-tox
modeling,sideeffect,andoff-targetpredictionaswellastarget
identification.

6. Pharmacophore Features
•Hydrogen Bond Donor
•Hydrogen Bond Acceptor
•Aromatic
•Hydrophobicity
•Hydrophilic

7. Pharmacophore modeling
•Pharmacophoremodelingismostoftenappliedto
virtualscreeninginordertoidentifymolecules
triggeringthedesiredbiologicaleffect.
•Forthispurpose,researcherscreatea
pharmacophoremodel(query)thatmostlikely
encodesthecorrect3Dorganizationoftherequired
interactionpattern.Dependingonhowmuchis
knownabouttheparticularproteintarget,different
optionsareavailabletoconstructsuchaquery

8. Types of Pharmacophore
modeling

9. Pharmacophore modeling
•Apharmacophoremodelistheensembleof
commonstericandelectronicfeaturesthatare
necessarytoensuretheoptimalmolecular
interactionswithaspecificbiologicaltargetandto
trigger(orblock)itsbiologicalresponse.Itcanbe
usedtorepresentandcharacterizemoleculeson
schematic2Dor3Dlevelbyidentifyingthe
essentialpropertiesofmolecularrecognition.

10. Pharmacophore modeling
Ligand-basedpharmacophoremodeling:
Intheabsenceofthemacromoleculartarget
structure,ligand-basedpharmacophoremodelingis
anessentialstrategyfordrugdiscovery.
Inthismethod,thecommonchemical
characteristicsfrom3Dstructuresofmultiple
knownligandsareextractedthroughligand
alignment,whichwouldrepresenttheessential
interactionsbetweenligandandpotential
macromoleculartarget.

11. Pharmacophore modeling
Structure-basedpharmacophoremodeling:
Thestructure-basedpharmacophoremodeling
generateschemicalfeaturesoftheactivesiteandthe
stericalrelationshipsfrom3Dstructureof
macromoleculartargetormacromolecule-ligand
complex.
Itprobesthepossibleinteractionsitesbetweenthe
macromoleculartargetandtheligands.