Petra/Osiris/Molinspiration and Molecular Docking Analyses of 3-Hydroxy-Indolin-2-one Derivatives as Potential Antiviral Agents

Background: Studies on the interaction between bioactive molecules and HIV-1 virus have been the focus of recent research in the scope of medicinal chemistry and pharmacology. Objective: Investigating the structural parameters and phys co-chem cal properties of elucidating and identifying the antiviral pharmacophore sites. Methods: 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 the enzyme. Results: The POM analyses of physico-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 is able to coordinate two transition metals. The increased activity of series 3a-5j, as compared to standard drugs, contains (Osp(2),O sp(3),O sp(2))-pharmacophore site. The increase in bio-activity from 4b (R-1, R-2 = H, H) to 3d (R-1, R-2 = 4-Br, 2-OCH3) could be attributed to the existence of 7E-charge transfer from para-bromo-phenyl to its amid group (CO delta---NW delta+). 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 the catalytic core domain of the enzyme. Conclusion: Study confirmed the importance of oxygen atoms, especially from the methoxy group of the phenyl ring, and electrophilic amide nitrogen atom for the formation of interactions.

Automated summary

This study focused on investigating the structural parameters and physico-chemical properties of 22 compounds with antiviral/antitumor/antibacterial potential. A computational model was used to identify the key physico-chemical parameters governing the bioactivity of these compounds, and molecular docking studies were conducted with HIV-1 integrase to analyze interactions at the binding site. The results highlighted the importance of oxygen atoms and electrophilic amide nitrogen atoms in forming interactions, and the activity enhancement of certain compounds was attributed to intra-molecular charge transfer.