In:
Medicinal Chemistry, Bentham Science Publishers Ltd., Vol. 18, No. 9 ( 2022-11), p. 970-979
Abstract:
HIV-1 subtype C protease is a strategic target for antiretroviral treatment.
However, resistance to protease inhibitors appears after months of treatment. Chromones and 2- biscoumarin derivatives show potential for inhibition of the HIV- subtype C protease. Objective: Different heterocyclic structures from the ZINC database were docked against Human
Immunodeficiency Virus-1 (HIV) subtype C protease crystal structure 2R5Q and 2R5P. The 5 best molecules were selected to be docked against 62 homology models based on HIV-protease sequences
from infants failing antiretroviral protease treatment. This experimentation was performed with two molecular docking programs: Autodock and Autodock Vina. These molecules were modified by
substituting protons with different moieties, and the derivatives were docked against the same targets. Ligand-protein interactions, physical/chemical proprieties of the molecules, and dynamics
simulations were analyzed. Methods: Docking of all of the molecules was performed to find out the binding sites of HIV-1 subtype C proteases. An in-house script was made to substitute protons of molecules with different moieties.
According to the Lipinski rule of five, physical and chemical properties were determined. Complexes of certain ligands-protease were compared to the protein alone in molecular dynamics
simulations. Results: From the first docking results, the 5 best (lowest energy) ligands (dibenz[a,h]acridine, dibenz[a, i]acridine, NSC114903, dibenz[c,h] acridine, benzo[a]acridine) were selected. The binding energy of the modified ligands increased, including the poorest-performing molecules. A correlation
between nature, the position, and the resulting binding energy was observed. According to the Lipinski rules, the physico-chemical characteristics of the five best-modified ligands are ideal for
oral bioavailability. Molecular dynamics simulations show that some lead-protease complexes were stable. Conclusion: Dibenz[a,h]acridine, dibenz[a, i] acridine, NSC114903, dibenz[c,h]acridine, benzo[ a]acridine and their derivatives might be considered as promising HIV-1 subtype C protease inhibitors. This could be confirmed through synthesis and subsequent in vitro assays.
Type of Medium:
Online Resource
ISSN:
1573-4064
DOI:
10.2174/1871520622666220202161543
Language:
English
Publisher:
Bentham Science Publishers Ltd.
Publication Date:
2022
SSG:
15,3
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