The Discovery of Indole-2-carboxylic Acid Derivatives as Novel HIV-1 Integrase Strand Transfer Inhibitors

Autor: Yu-Chan Wang, Wen-Li Zhang, Rong-Hong Zhang, Chun-Hua Liu, Yong-Long Zhao, Guo-Yi Yan, Shang-Gao Liao, Yong-Jun Li, Meng Zhou
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Molecules, Vol 28, Iss 24, p 8020 (2023)
Druh dokumentu: article
ISSN: 1420-3049
DOI: 10.3390/molecules28248020
Popis: As an important antiviral target, HIV-1 integrase plays a key role in the viral life cycle, and five integrase strand transfer inhibitors (INSTIs) have been approved for the treatment of HIV-1 infections so far. However, similar to other clinically used antiviral drugs, resistance-causing mutations have appeared, which have impaired the efficacy of INSTIs. In the current study, to identify novel integrase inhibitors, a set of molecular docking-based virtual screenings were performed, and indole-2-carboxylic acid was developed as a potent INSTI scaffold. Indole-2-carboxylic acid derivative 3 was proved to effectively inhibit the strand transfer of HIV-1 integrase, and binding conformation analysis showed that the indole core and C2 carboxyl group obviously chelated the two Mg2+ ions within the active site of integrase. Further structural optimizations on compound 3 provided the derivative 20a, which markedly increased the integrase inhibitory effect, with an IC50 value of 0.13 μM. Binding mode analysis revealed that the introduction of a long branch on C3 of the indole core improved the interaction with the hydrophobic cavity near the active site of integrase, indicating that indole-2-carboxylic acid is a promising scaffold for the development of integrase inhibitors.
Databáze: Directory of Open Access Journals