Background: Studies on the interaction between bioactive molecules and HIV-1 virus has been the focus of recent research in the scope of medicinal chemistry and pharmacology.
Objective: Investigating the structural parameters and physic-chemical properties of elucidating and identifying of the antiviral pharmacophore sites.
Method: A mixed computational Petra/Osiris/Molinspiration/DFT (POM/DFT) based model has been developed for the identification of physico-chemical parameters governing the bioactivity of 22 3-hydroxy-indolin-2-one derivatives of diacetyl-L-tartaric acid and aromatic amines containing combined antiviral/antitumor/antibacterial pharmacophore sites. Molecular docking study was carried out with HIV-1 integrase (pdb ID: 5KGX) in order to provide information about interactions in the binding site of enzyme.
Results: The POM analyses of physic-chemical properties and geometrical parameters of compounds 3a-5j, show that they are bearing a two combined (O,O)-pockets leading to a special platform which able to coordinate two transition metals. The increased activity of series 3a-5j, as compared to standard drugs, contains an (Osp2,O sp3,O sp2)-pharmacophore site. The increase of bioactivity from 4b (R1, R2 = H, H) to 3d (R1, R2 = 4-Br, 2-OCH3) could be attributed to the existence of pi-charge transfer from para-bromo-phenyl to its amid group (COδ---NHδ+). Similar to the indole-based reference ligand (pdb: 7SK), compound 3d forms hydrogen bonding interactions between the residues Glu170, Thr174 and His171 of HIV-1 integrase in catalytic core domain of enzyme.
Conclusion: Study confirmed the importance of oxygen atoms, especially from the methoxy group of the phenyl ring, and electrophilic amide nitrogen atom for formation of interactions.