A seminar on design of ligands for known
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  • 1. A SEMINAR ON DESIGN OF LIGANDS FOR KNOWN RECEPTORS DEPARTMENT OF PHARMACEUTICAL CHEMISTRY MCOPSSUBMITTED TO SUBMITTED BYDr Suvarna G. kinni Shikha TyagiAsst. professor 100602017
  • 2. CONTENTSINTRODUCTIONSITE IDENTIFICATIONSITE CHARACTERISATION• HYDROGEN BONDING AND OTHER GROUPS• ELECTROSTATIC AND HYDROPHOBIC FIELDDESIGN OF LIGANDS• VISUALLY ASSISTED DESIGN• 3-D DATABASE• DE NOVO DESIGNCALCULATION OF AFFINITY
  • 3. INTRODUCTIONLIGAND A ligand (from the Latin ligandum, binding) is a substance that forms a complex with a biomolecule to serve a biological purpose.
  • 4. RECEPTOR: A RECEPTOR IS A PROTEIN MOLECULE, EMBEDDED IN EITHER THE PLASMA MEMBRANE OR THE CYTOPLASM OF A CELL, TO WHICH ONE OR MORE SPECIFIC KINDS OF SIGNALING MOLECULES MAY ATTACH. Cytoplasmic receptorMembrane receptor
  • 5. PHARMACOPHORE: A PHARMACOPHORE IS AN ABSTRACT DESCRIPTION OF MOLECULAR FEATURES WHICH ARE NECESSARY FOR MOLECULAR RECOGNITION OF A LIGAND BY A BIOLOGICAL MACROMOLECULE. THE IUPAC DEFINES A PHARMACOPHORE TO BE "AN ENSEMBLE OF STERIC AND ELECTRONIC FEATURES THAT IS NECESSARY TO ENSURE THE OPTIMAL SUPRAMOLECULAR INTERACTIONS WITH A SPECIFIC BIOLOGICAL TARGET AND TO TRIGGER (OR BLOCK) ITS BIOLOGICAL RESPONSE.
  • 6. DESIGN OF LIGANDS TWO TYPES LIGAND BASED AND STRUCTURE BASED STRUCTURE BASED LIGAND BASED
  • 7. SITE IDENTIFICATION  3-D STRUCTURE BY NMR AND X –RAY CRYSTALLOGRAPHY  BUT IT DOES NOT GUARANTEE THE SITE OF ACTION BY LIGANDS SOMETIMES CONFORMATIONAL CHANGES OCCURES DURING THE BINDING WHICH ARE NOT REFLECTED IN 3-D STRUCTURE FOR EXAMPLE : WHEN MVT-101 A ANTI HIV DRUG BINDS TO THE HIV PROTEASE ENZYME CONFORMATIONAL CHANGES OCCURSthe two β-strand flaps have been folded in, to complete the active site of HIVprotease, the important interactions for recognition in this proteolytic systemNMR- NOE CAN HELP IN INDENTIFICATION OF SUCH CONFORMATIONAL CHANGES.
  • 8. Figure 3.14. Ribbon diagram of HIV-1 protease in the absence of inhibitor (a) and when bound to the inhibitor MVT-10103). Diagrams based on crystal structures as reported by Miller et al. Ribbon diagram of HIV-1 protease in the absence of inhibitor (a) and when boundto the inhibitor MVT-101.
  • 9. DYNAMICS OF RECEPTORSIT IS VERY IMPORTANT TO ANSWER SOME QUESTIONSQ1 HOW STABLE IS THE ACTIVE SITE TO MODIFICATION IN THE LIGAND????????:.Q1 Is THERE ANY ALTERNATIVE BINDING SITE WHICH IS COMPETING WITHTHE BINDING SITE OF LIGAND.????????FOR EXAMPLE-DIFFICULTY IN INTERPRETATION OF BINDING SITE AS A RESULT OF LIGANDMODIFICATION OCCURS WHEN AN ANALOG DESIGN IS BIND TO THE SPECIFICSITE ON HEMOGLOBIN .ACTUALLY THIS ANALOG FOUND A MOREAPROPREIATE SITE WITHIN THE PACKED SIDE CHAIN OF THE PROTEINMOLECULE .THIS EMPHASIZE THE DYNAMICS OF PROTEIN MOLECULE.SOLUTION – 3-D STRUCTURE OF CAVITY AND POCKETS ASSIST THEBINDING INTERACTION AND DESIGN OF NOVEL LIGANDS
  • 10. HOW IT IS DONE????????????????DOCKINGIT EXPLORE THE STERIC COMPLEMENTORY BETWEEN LIGANDS ANDRECEPTORS OF 3-D STRUCTURE USING THE MOLECULAR SURFACE OFRECEPTORSUSING THE MOLECULAR SURFACE OF RECEPTORS VOLUMETRICAPPOXIMATION OF SURFACE IS DONE. IN THIS METHOD SET OF SPHERE OF VARIOUS SIZES PACKEDMATHEMATICALLY WITHIN IN IT.THE DISTANCE BETWEEN THE CENTERS SERVES AS THE A COMPACTREPRESENTATION OF SHAPE OF CAVITY LIGANDS ALSO CHARACTERISED IN THE SAME WAY AND THE DISTANCEMATRIX OF LIGAND AND THE RECEPTOR IS COMPAREDAND THE POTENTIAL LIGAND IS SELECTED
  • 11. CHARACTERISATION SITEONCE THE SITE IS IDENTIFIED IT IS CHARACTERISED FOR VARIOUSPARAMETERS AS DESCRIBED BELOW1 HYDROGEN BONDING AND OTHER GROUPSIN EVALUATING THE POTENTIAL LIGANDS IT IS NECESSORY TO HAVETHE KNOWLEDGE OF OPTIMAL POSITIONS OF THE FUNCTIONAL GROUPSGRID- ALLOWS A PROBE ATOM OR GROUP TO EXPLORE RECEPTORSITE CAVITY ON A LATTICE OR A GRID WHILE ESTIMATING THEENTHALPY OF INTERACTION.3-D CONTOUR MAP IS GENERATED FROM THE INTERACTION ENERGYWHICH GIVES THE GRAPHICAL REPRESENTATION OF POSITION OFFUNCTIOL GROUP AND HENCE THE HYDROGEN BONDING .
  • 12. COMFA-COMPARATIVE MOLECULAR FIELD ANALYSIS COMPUTE INTERACTION OF PROBE WITH MOLECULE AT EACH POINTACTIVITY IS DIRECTLY RELATED TO STRUCTURAL PROPERTIES OF SYSTEMSTEPS INVOLVEDHYPOTHESIZE MECHANISM FOR BINDING BY IDENTIFING STRUCTURE OFBINDING SITEFIND EQUILIBRIUM GEOMETRYCONSTRUCT LATTICE OR GRID OF POINTSCOMPUTE INTERACTION OF PROBE WITH MOLECULE AT EACH POINTAPPLY PLSPREDICT
  • 13. DYLOMS-ELIMINATE THE PROBLEM OF RESOLUTION BY GRID .IT ORIENT THE FUNCTIONAL GROUP FOR OPTIMAL INTERACTION WITHTHE BINDING SITE AND GENERATE NOVEL STRUCTURE.HOW???MULTIPLE COPIES OF LIGANDS IS DISTRIBUTED AT THE BINDING SITE BYSIMULATION AND THEIR RELATIVE DISTRIBUTION IS EXAMINED.POPULATION OF LIGANDS IS CONCENTRATED ON OPTIMAL BINDINGSITE . LIGANDS ARE CONNECTED WITH THE MOST ENERGETICALLY FAVOUREDBINDING SITE (I.e THE C-C OVERLAP OF THE LIGAND WITH THE FRAGMENTOF BINDING SITE)NOVEL LIGANDS ARE DESIGNED
  • 14. ELECTROSTATIC AND HYDROPHOBIC INTERACTIONSSURFACE DISPLAYS THE PROPERTIES LIKE HYDROPHOBICITY ANDELECTROSTATIC FIELDMOLECULAR SURFACES DISPLAYS MAY BE COLOR CODED TO DEPICT THEVARIOUS PROPERTIES.SURFACE CAN BE DISPLAYED BY DOTS OR CONTOURS.CAVITY DISPLAY-THE LOCI OF THE FILLER ATOMS PACKING THE CAVITY ISCOMPUTEDOUTRMOST LAYER OF THE FILLER SOLID IS IDENTIFIED .THIS SURFACE DISPLAYS THE INTERFACE BETWEEN BINDING SITE AND THELIGAND ELCTROSTATIC INTERACTION.
  • 15. AT EACH POINT ELECTROSTATIC POTENTIAL IS CALCULATED.VALUES ARE ASSIGNED BY COLOR AND DISPLAYEDREGIONS OF ELECTROSTATIC COMPLEMENTARITY AND DISPARITY ARE DOCKEDA ROUGH APPROXIMATION OF COMPLEMENTARITY IS COMPUTED BYMULTIPLYING THESE POTENTIAL TOGETHERNEGATIVE PRODUCT FAVOURS BINDING AND THE POSITIVE UNFAVOURABLE FORBINDINGNOVEL LIGAND IS DESIGNED IN THIS WAY.
  • 16. DESIGN OF LIGANDSVISUALLY ASSISTED DESIGNBY DIRECTLY EXAMINE THE LIGAND WE CAN SELECT THE REGIONS WHEREMODIFICATIONS CAN BE MADE.BUT THIS IS DIFFICULT FOR THE RECEPTOR –LIGAND GAP REGION THIS IS DONE BY THECAVITY DISPLAY INTHIS APPROACH THE NEAREST DISTANCE BETWEEN THE ATOMS IN THE GAP ISCALCULATED THAT IS THE SURFACE TO SURFACE DISTANCE.COLOR CODING IS DONE TO DISPLAY THIS .
  • 17. 3-D DATABASESCAMBRIDGE STRUCTURAL DATA BASES—90,000 STRUCTUREBROOKHAVEN PROTEIN DATABANK –CONTAINS THE CRYSTALS CO-ORDINATES OF PROTEINS AND THE OTHERBIOMOLECULE THIS CONSIST OF LOW ENERGY CONFORMER THAT IS READILY ATTAINABLE INSOLUTION OR THE RECEPTORS3-D DATABASE IS SEARCHED BY USING A QUERY FOR FRAGMENT THAT CONTAINTHE PHARMACOPHORIC FUNCTIONAL GROUP.IN PROPER 3-D DIMENSIONALORIENTATION.USING FRAGNMENTS AS THE BUILDING BLOCKS COMPLETE NOVEL STRUCTUREMAY BE GENERATED BY ASSEMBLY AND PRUNING
  • 18. PHARMACOPHORE MATCHING ESTROGEN MOLECULE
  • 19. CONCORD CHEMICAL ABSTRACTS ARE GENERATED BY USING THIS7,00,000 ENTERIESTHIS IS NONCRYSTALLOGRAPHIC DATABASEIT IS USED WHEN THE CRYSTAL STRUCTURE OF LIGNAD – RECEPTORCOMPLEX IS KNOWN.AND ITS BINDING IS WELL UNDERSTOOD IN TERMS OFFUNCTIONAL GROUP.IN SUCH CASE LIGANDS CAN BE GENERATED BY USINGTHE SCAFFOLDS THAT POSITION THE PHARMACOPHORIC GROUP OR THEIRISOSTERS IN THE CORRECT 3-D ARRANGEMENTMOLPAT IS THE FIRST PROTOTYPE TO SEARCH FOR MOLECULE THAT MATCH 3-DPHARMACOPHORIC PATTERN.IT PERFORMS ATOM BY ATOM SEARCH TO VERIFY COMPARABLEINTERATOMIC DISTANCES BETWEEN THE PATTERN AND THE CANDIDATE.
  • 20. CAVEATTO IDENTIFY THE CYCLIC STRUCTURESALLADIN,3-D SEARCH,MACCS-3-DFOR MOLECULAR PROPERTIES LIKE ATOM TYPE ,BONDANGLE,TORSIONAL ANGLE,LIGAND RECEPTOR COMPLEMENTORY.CHEM-X CONFORMATIONAL SEARCHMDS FOR THE CONFORMATIONAL SEARCH ,BINDING ENERGY ,FORCEFIELDS, 3 –D STRUCTURES.VARIOUS MODELS LIKE BALL –STICK MODELSPACE MODEL
  • 21. SHAPE MATCHING ALGORITHM Sheridan et al screened candidate compounds to select those whose volumes would fit within the combined volumes of known active compounds. BROMOPERIDOL JG-365
  • 22. FOUNDATION-3-D DATABASE OF CHEMICAL STRUCTURE FOR A USER DEFINED QUERYCONSISTING OF THE CO-ORDINATES OF ATOMS AND BONDALL POSSIBLE STRUCTURES THAT CONTAINS ANY COMBINATION OF AUSER DEFINED MINIMUM NUMBER OF MATCHING ATOM AND BONDS ARERETERIVED..SPLICE- TRIMS THE MOLECULE FOUND FROM THE DATABASE TO FIT WITHINTHE ACTIVE SITE AND LOGICALLLY COMBINE THEM BY OVERLAPPING BONDSTO MAXIMIZE INTERACTION WITH THE SITE.
  • 23. DE NOVO DESIGNDrug discovery and development is a complex, lengthy process, and failure of a candidatemolecule can occur as a result of a combination of reasons, such as poor pharmacokinetics, lack oefficacy, or toxicity. De novo drug design involves searching an immense space of feasible, druglike molecules toselect those with the highest chances of becoming drugs using computational technology.Traditionally, de novo design has focused on designing molecules satisfying a singleobjective, such as similarity to a known ligand or an interaction score, and ignored the presence othe multiple objectives required for druglike behavior. Recently, methods have appeared in the literature that attempt to design molecules satisfyingmultiple predefined objectives and thereby produce candidate solutions with a higher chance ofserving as viable drug leads BR geBRIDGE is based on geometric generation of possible cyclic compounds as scaffolds, ofgiven constraints derived from the types of chemistry the chemist is willing to consider. co sc gi deLUDI to construct ligands for active sites with an empirical scoring functionto evaluate their construction.
  • 24. CALCULATION OF AFFINITYCALCULATION OF BINDING AFFINITY BASED ON THE 3- D STRUCTUREWILLIAM USED VANCOMYCIN-PEPTIDE COMPLEX TO CALCULATE BINDING AFFINITYIN TERMS OF GIBBS FREE ENERGY
  • 25. ∆G(Trans + rot) - free energy associated with translational and rotational freedomof the ligand. This has an adverse effect on binding of 50-70 kJ/mol (12-17 kcallmol)at room temperature for ligands of 100-300 Dalton, assuming complete loss ofrelative translational and rotational freedom∆Grotors -free energy associated with the number of rotational degrees of freedomfrozen. This is 5-6 kJ/mol (1.2-1.6 kcal/mol) per rotatable bond, assuming completeloss of rotational freedom.∆H c o n f o m- is the strain energy introduced by complex formation (deformationin bond lengths, bond angles, torsional angles, etc.∑∆ Gi is the sum of interaction free energies between polar groups∆Gvdw-ENERGY DERIVED FROM THE ENHANCED VANDERWAALS INTERACTIONS∆GH- FREE ENERGY ATTRIBUTED TO HYDROPHOBIC INTERACTION
  • 26. REFERENCESBURGERS “MEDICINAL CHEMISTRY AND DRUG DISCOVERY”, 5thEdition,Vol-I,Page no-599-612http://pubs.acs.org/doi/abs/10.1021/ci800308hhttp://en.wikipedia.org/wiki/File:biocomputing and drug design.
  • 27. THANkU