In-Silico Screening and Design of Low Molecular Weight Cyclophilin-A Inhibitors That Assist HIV-1 Capsid Assembly

A network of protein iteration has recently been identified in the enzyme cyclophilinA (CypA) that is associated with its peptidylprolylcis-trans isomerization activity. This work presents the results from the characterization of this network during the isomerization of the Gly89- Pro90 peptide bond in the N-terminal domain of the capsid protein (CA). A variety of computational studies are utilized to investigate the protein CypA-CAN complex. Interaction energy is used for a detailed investigation of the protein–protein interactions in the CypA-CAN complex. The results show that CAN residues His87Ala-Gly-Pro-Ile-Ala92 form the majority of the interactions with CypA residues. In this work, molecular modeling studies were performed to develop a predictive Common Pharmacophore Hypothesis (CPH). A total of 64 molecules from previously reported literature, were selected for pharmacophore refinement and 3D-QSAR studies. The best pharmacophore hypothesis AADR, which had two hydrogen bond acceptors, a hydrogen bond donor, and an aromatic ring, was obtained. The model showed good r2and q2values of 0.923and 0.631respectively. The developed Pharmacophore model was validated by predicting the activity of test set molecules. The CPH obtained was used as a template for virtual screening. The results obtained from 3D-QSAR, Screening and docking studies were used for rational design of potential inhibitors of Cyclophilin – A.