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Current Computer-Aided Drug Design

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ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

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Research Article

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

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

Volume 17, Issue 1, 2021

Published on: 26 December, 2019

Page: [123 - 133] Pages: 11

DOI: 10.2174/1573409916666191226110029

Price: $65

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Abstract

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 physico-chemical 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 (Osp2,O sp3,O sp2)-pharmacophore site. The increase in bioactivity from 4b (R1, R2 = H, H) to 3d (R1, R2 = 4-Br, 2-OCH3) could be attributed to the existence of π-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 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.

Keywords: 3-Hydroxy-indolin-2-ones, POM analyses, HIV antiviral activity, pharmacophore, molecular docking, HIV-1 integrase.

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