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

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Author(s): Taibi Ben Hadda*, Vesna Rastija*, Faisal AlMalki, Abderrahim Titi, Rachid Touzani, Yahia N. Mabkhot, Shah Khalid, Abdelkader Zarrouk, Bina S. Siddiqui.

Journal Name: Current Computer-Aided Drug Design

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Abstract:

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.

Keywords: 3-Hydroxy-indolin-2-ones, POM analyses, HIV antiviral activity, Pharmacophore, Molecular docking, HIV-1 integrase

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(E-pub Ahead of Print)
DOI: 10.2174/1573409916666191226110029
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