Proposing De-Novo Generated, Iteratively Optimized New Lead Molecules Trageting Hiv-1 Protease

Abstract

HIV-1 protease is a major enzyme that plays an importantrole in the replication of virus. The energy refinedstructures of target were modelled by modeller 9v l OusingPDB entry lLVl as template. Ligsite program revealedthree potential ligand binding ite where the pkt-69 isfound to be more favourable containing critical aspartic,threonine & glycine residues (D25 , T26 and G27).Heuristic search revealed Methyl-formamide as seedmolecule for de-nova generation of structurallycomplimented lead molecules. LigbuilderVl.2 growingstrategy was used for de-novo generation with 10population cycles. Binding energies were examined byAutodock 4 .2.3 for all the designed ligand molecules.Iterative in-silica optimization of the examined moleculeswere done and finally de-novo generatedO=CO/C(O/C(=C/C/C=C/C)C(N C= O)Cc l cc(ccc 1\C=C\O)C(O)CC)=C was found as the best fit over rule of 5 andother ADME parameters. Affinity analysis suggested thedirect interaction of designed molecules with catalyticaspartate, threonine & glycine (D25,T26 and G27) havinggood number of VdW interactions. Thu , the designedmolecule could possibly inhibit the action of HIV PRlpreventing the cleavage of polypeptides and thereby stopsthe replication of HIV virus.