Taibi Ben Hadda*, Vesna Rastija*, Faisal AlMalki, Abderrahim Titi, Rachid Touzani, Yahia N. Mabkhot, Shah Khalid, Abdelkader Zarrouk and Bina S. Siddiqui Pages 1 - 11 ( 11 )
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.
3-Hydroxy-indolin-2-ones, POM analyses, HIV antiviral activity, Pharmacophore, Molecular docking, HIV-1 integrase
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm AlQura University, Makkah, Department of Agroecology and Environmental Protection, Faculty of Agrobiotechnical Sciences Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm AlQura University, Makkah, LCAE-LCM Laboratories, Faculty of Sciences, University Mohammed Premier, Oujda, LCAE-LCM Laboratories, Faculty of Sciences, University Mohammed Premier, Oujda, Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha, Department of Botany, Islamia College, Peshawar, Laboratory of Materials, Nanotechnology and Environment, Faculty of Sciences, Mohammed V University, Agdal-Rabat, HEJ Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi