Pharmacophore Modeling and Docking Techniques.ppt

Pharmacophore Modeling and Docking Techniques.ppt

1. TITLE-
“Pharmacophore Modeling and
Docking Techniques”
Subject Code -BP601T
Unit No. -5
Lecture No. -3
By -Dr. Mohit Gupta
Shri Ram Murti Smarak College of
Engineering & Technology,
Bareilly (Pharmacy)

2. •Medicinalchemiststodayarefacinga
seriouschallengebecauseofthe
increasedcostandenormousamountof
timetakentodiscoveranewdrug,and
alsobecauseoffiercecompetition
amongstdifferentdrugcompanies

3. PHARMACOPHORE-
Apartofamolecularstructurethatisresponsibleforaparticular
biologicalorpharmacologicalinteractionthatitundergoes.
Apharmacophoreisanabstractdescriptionofmolecularfeatures
thatarenecessaryformolecularrecognitionofaligandbya
biologicalmacromolecule.
PHARMACOPHOREMODEL-
Apharmacophoremodelistheensembleofcommonstericand
electronicfeaturesthatarenecessarytoensuretheoptimal
molecularinteractionswithaspecificbiologicaltargetandto
trigger(orblock)itsbiologicalresponse.

4. Whitesticksrepresentthecarbonatomsof
thebenzodiazepinediazepam.
whilegreenrepresentscarbonatomsofthe
nonbenzodiazepineCGS-9896.
Redandbluesticksareoxygenandnitrogen
atomsthatarepresentinbothstructures.
TheredsphereslabeledH1andH2/A3are,
respectively,hydrogenbonddonatingand
acceptingsitesinthereceptor,whileL1,L2,
andL3denotelipophilicbindingsites.
AN EXAMPLE OF A PHARMACOPHORE MODEL OF
THEBENZODIAZEPINEBINDING SITE ON THEGABA
ARECEPTOR

5. MOLECULAR MODELLING-
MolecularModellingisacollectionof(computerbased)techniquesfor
deriving,representingandmanipulatingthestructuresandreactions
ofmolecules,andthosepropertiesthataredependentonthesethree
dimensionalstructures.
MOLECULARDOCKING-
Moleculardockingis the study of how two or more molecular structures (e.g.,
drug and enzyme or protein) fit together.
Dockingis a molecular modeling technique that is used to predict how a protein
(enzyme) interacts with small molecules (ligands).
Inthefieldofmolecularmodeling,dockingisamethodwhichpredictsthe
preferredorientationofonemoleculetoasecondwhenboundtoeachotherto
formastablecomplex.

6. Pharmacophore
A pharmacophore that indicates the key features of a series of
active molecules.
H HBD HBA R
In drug design, the term 'pharmacophore‘ refers to a set of
features that is common to a series of active molecules.
Hydrogen-bonddonorsandacceptors,positivelyand
negativelychargedgroups,andhydrophobicregionsare
typicalfeatures.
We will refer to such features as 'pharmacophoric groups'.

8. •Defines the important groups involved inbinding
•Defines the relative positions of the bindinggroups
•Need to know ActiveConformation
•Important to DrugDesign
•Important to DrugDiscovery

9. Bioisosteres
Bioisosteres,whichareatoms,functionalgroupsor
moleculeswithsimilarphysicalandchemicalproperties
suchthattheyproducegenerallysimilarbiological
properties

10. 3D-Pharmacophores
A three-dimensional pharmacophore specifies the spatial relation-
ships between the groups
Expressed as distance ranges, angles and planes
A commonly used 3D pharmacophore for antihistamines contains
two aromatic rings and a tertiary nitrogen

14. INTRODUCTION TO RATIONAL DRUGDESIGN
Rationaldrugdesignisaprocessinwhichfindingofnewmedication
isbasedonknowledgeofbiologicaltarget.
Itinvolvesdesignofsmallmoleculesthatarecomplementaryin
shapeandchargetobimoleculartarget.
Drugdesignfrequentlybutnotnecessarilyreliesoncomputer
modelingtechniques.Thistypeofmodelingissometimesreferredto
ascomputer-aideddrugdesign.
Thetherapeuticantibodiesareanincreasinglyimportantclassof
drugsandcomputationalmethodsforimprovingtheaffinity,
selectivity,andstabilityoftheseprotein-basedtherapeuticshavealso
beendeveloped

15. METHODS OF RATIONAL DRUG DESIGNING :-
1.Structure Based Drugdesign
2.Ligand based drugdesign.
3.Fragment Based drugdesign

16. DOCK
DOCKisafragmentbasedmethodusingshapeandchemical
complementarymethodsforcreatingpossibleorientationsforthe
ligand.
Theseorientationscanbescoredusingscoringfunctionssuchas
solvationorhydrophobicity.

17. STEPS INVOLVED DOCKING PROGRAM
1.Get the complex from protein data bank
2.Clean the complex
3.Addthe missing hydrogen/sidechain atoms andminimize the complex
4.Clean the minimized complex
5.Separate the minimized complex in macromolecule (lock) and ligand (key)
6.Prepare the docking suitable files for lock and key
7.Prepare all the needing files for docking
8.Run the docking
9.Analyze the docking results

18. MOLECULAR DOCKING
It is a method which predicts the preferred orientation of one ligand when
bound in an active site to form a stable complex.
Docking is used for finding binding modes of protein with ligands or
inhibitors. They are able to generate a large number of possible structures.
In molecular docking, we attempt to predict the structure ofthe
intermolecular complex formed between two or more molecules.

20. Fig :-Mechanism of Dockingprogram

22. TYPES OF DOCKING :-
Therearetwotypesofdockingthatare:-
1.Rigiddocking:Inrigiddockingthemoleculesarerigid,in3Dspaceof
oneofthemoleculewhichbringsittoanoptimalfitwithothermoleculein
termsofscoringfunction.Alsotheinternalgeometryofboththereceptorand
ligandarerigid.
2.Flexibledocking:Inthistypeofdockingthemoleculesareflexible,
conformationsofthereceptorandligandmoleculesastheyappearincomplex.

23. Rigiddocking
Flexibledocking

24. TYPES OF DOCKING STUDIES:-
1.Protein-Proteindocking:Theseinteractionsoccurbetweentwo
proteinsthataresimilarinsize.Conformationalchangesarelimitedby
stericconstraintsandthusaresaidtoberigid.

25. 2.ProteinReceptor-Liganddocking:proteinreceptor-ligand
dockingisusedtocheckthestructure,positionandorientationofa
proteinwhenitinteractswithsmallmoleculeslikeligands.Protein
receptor-ligandmotifsfittogethertightly,andareoftenreferredto
asalockandkeymechanism.

26. Protein -Ligand Protein -Protein
Protein -Nucleotide

32. TYPES OF INTERACTIONS :-
Interactionsbetweenparticlescanbedefinedasaconsequenceofforcesbetween
themoleculescontainedbytheparticles.Theseforcesaredividedintofour
categories:-
1.Electrostaticforces-Forceswithelectrostaticoriginduetothecharges
residinginthematter.Themostcommoninteractionsarecharge-charge,charge
dipoleanddipole-dipole.
2.Electrodynamicsforces-ThemostwidelyknownistheVanderWaals
interactions.
3.Stericforces-Stericforcesaregeneratedwhenatomsindifferentmolecules
comeintoveryclosecontactwithoneanotherandstartaffectingthereactivityof
eachother.Theresultingforcescanaffectchemicalreactionsandthefreeenergyof
asystem.
4.Solvent-relatedforces-Theseareforcesgeneratedduetochemicalreactions
between the solvent and the protein or ligand. Examples are Hydrogen bonds
(hydrophilic interactions) and hydrophobic interactions.

33. FACTORS AFFECTING DOCKING :-
The factors affecting docking are of two different forces that are as follows:-
1.Intra-molecular forces:-
a.Bond length
b.Bond angle
c.Dihedralangle
2.Inter-molecular forces:-
a.Electrostatic
b.Dipolar
c.H-bonding
d.Hydrophobicity
e.Van der Waal’sforces

34. STAGES OF DOCKING :-
1.Target / Receptor selection andpreparation
2.Ligand selection andpreparation
3.Docking
4.Evaluating dockingresults

35. PREPARATION STEPS OF MOLECULAR DOCKING
Sources
A target 3D structure is required!
The PDB (protein databank)
➔X-ray diffraction
●No size limit
●More accurate
●Unique structure (of the crystal)
●Crystallization problems
●Hydrogen are missed
➔NMR
●Lowest accuracy
●Solution structure
●Size limit around 150 residues
(for a protein)
●Average structure
➔Homology modeling
●Free and quick
●No experimental
●Low precision of side chains
●Sequence similarity or identity?
Target structure

36. PREPARATION STEPS OFMOLECULARDOCKING
Accuracy is an important parameter:RX
Here precision, accuracy is verygood.
Resolution

37. Targetstructure
Resolution
A protein alpha-helix with differentresolution
Preparation steps of moleculardocking

38. PREPARATION STEPS OFMOLECULARDOCKING
Targetstructure
Resolution
InNMRtheresolutionishardtodeterminenumerically:
GenerallywelookattheRMSD(Inbioinformatics,theroot-mean-square
deviationofatomicpositionsisthemeasureoftheaveragedistance
betweentheatomsofsuperimposedproteins.NotethatRMSD
calculationcanbeappliedtoother,non-proteinmolecules,suchassmall
organicmolecules)orthenumberofrestraintsbyresidue.
As an interdisciplinary field of science,bioinformaticscombines biology, computer
science, information engineering, mathematics and statistics to analyze and interpret
the biological data.Bioinformaticshas been used for in silico analyses of biological
queries using mathematical and statistical techniques.

39. TYPICAL DOCKING WORKFLOW
TARGET
SELECTION
LIGAND
SELECTION
TARGET
PREPARATION
EVALUATING
DOCKING RESULT
DOCKING
LIGAND
PREPARATION

40. CommonSoftware'sUsedforDocking Purpose:-
Sr. No.Docking
Program
Year
Published
Docking Approach
1. DOCK 1988 Shape fitting
(sphere sets)
2. Auto Dock 1990 Genetic
Algorithm, Simulated Annealing
3. Flex X 2001 Incremental construction
4. FRED 2003 Shape fitting
5. VLifeMDS Protein-ligand based design
6. FLOG 1994 Rigid body docking program
7. HADDOCK 2003 Protein-Protein docking, Protein-
Ligand docking
57

42. VLifeMDS
Ithasanpowerfultoolstoconductproteinandligandlevelstudies
throughmolecularmodelingandsimulation.
VLifeMDSisusefulinidentifyingthekeyresiduesforprotein–ligand
interactionsleadinginoptimizationofligand.

43. IMPORTANCE OF DOCKING :-
Dockingisfrequentlyusedtopredictthebindingorientationofsmall
moleculedrugcandidatestotheirproteintargetsinordertointurn
predicttheaffinityandactivityofthesmallmolecule.Hencedocking
playsanimportantroleintherationaldesignofdrugs.
Theassociationsbetweenbiologicallyrelevantmoleculessuchas
proteins,nucleicacid,carbohydratesandlipidsplayacentralrolein
signaltransduction.Furthermore,therelativeorientationoftwo
interactingpartnersmayaffectthetypeofsignalproduced(E.g.-
AgonismVsAntagonism).Thereforedockingisusefulinpredicting
both strength and type of signalproduced.

45. Dr. Mohit Gupta
M.Pharm, Ph.D
Associate Professor,Shri Ram Murti Smarak College of
Engineering & Technology, Bareilly (Pharmacy)
Ram Murti Puram, Bhojipura,13K.M. Bareilly-Nainital Highway,
Bareilly, U.P., India.Pin Code-243202
E-mail:[email protected]
Contact No. : [phone], [phone]