Proposing de-novo Generated, Iteratively Optimized New Lead Molecules Targeting HIV-1 PROTEASE

HIV-1 protease is a major enzyme that plays an important role in the replication of virus. The energy refined structures of target were modelled by modeller 9v10 using PDB entry 1LV1 as template. Ligsite program revealed three potential ligand binding sites where the pkt-69 is found to be more favourable containing critical aspartic, threonine & glycine residues (D25, T26 and G27). Heuristic search revealed Methyl-formamide as seed molecules for de-novo generation of structurally complimented lead molecules. LigbuilderV1.2 growing strategy was used for de-novo generation with 10 population cycles. Binding energies were examined by Autodock 4.2.3 for all the designed ligand molecules. Iterative in-silico optimization of the examined molecules w e r e d o n e a n d f i n a l l y d e - n o v o g e n e r a t e d O=CO/C(O/C(=C/C/C=C/C)C(NC=O)Cc1cc(ccc1C=C O)C(O)CC)=C was found as the best fit over rule of 5 and other ADME parameters. Affinity analysis suggested the direct interaction of designed molecules with catalytic aspartate, threonine & glycine (D25,T26 and G27) having good number of VdW interactions. Thus, the designed molecule could possibly inhibit the action of HIV PR1 preventing the cleavage of polypeptides and thereby stops the replication of HIV virus.