A consensus reverse docking approach for identification of a competitive inhibitor of acetyltransferase enhanced intracellular survival protein from Mycobacterium tuberculosis.

Autor: Santos-Júnior PFDS; Pharmaceutical Sciences Graduate Program (PPGCS), Federal University of Sergipe, São Cristóvão, Sergipe 49100-001, Brazil., Batista VM; Research Group of Biological and Molecular Chemistry, Institute of Chemistry and Biotechnology, Federal University of Alagoas, Lourival Melo Mota Avenue, AC. Simões campus, 57072-970 Alagoas, Maceió, Brazil., Nascimento IJDS; Post-Graduation Program of Pharmaceutical Sciences, Pharmacy Department, State University of Paraíba, Campina Grande, Brazil., Nunes IC; Research Group of Biological and Molecular Chemistry, Institute of Chemistry and Biotechnology, Federal University of Alagoas, Lourival Melo Mota Avenue, AC. Simões campus, 57072-970 Alagoas, Maceió, Brazil., Silva LR; Research Group of Biological and Molecular Chemistry, Institute of Chemistry and Biotechnology, Federal University of Alagoas, Lourival Melo Mota Avenue, AC. Simões campus, 57072-970 Alagoas, Maceió, Brazil., Costa CACB; Department of Chemistry, Federal Institute of Alagoas, Maceió campus, Mizael Domingues Street, 57020-600 Maceió, Alagoas, Brazil., Freitas JD; Department of Chemistry, Federal Institute of Alagoas, Maceió campus, Mizael Domingues Street, 57020-600 Maceió, Alagoas, Brazil., Quintans-Júnior LJ; Pharmaceutical Sciences Graduate Program (PPGCS), Federal University of Sergipe, São Cristóvão, Sergipe 49100-001, Brazil., Araújo-Júnior JX; Laboratory of Medicinal Chemistry, Institute of Pharmaceutical Sciences, Federal University of Alagoas, Lourival Melo Mota Avenue, AC. Simões campus, 57072-970 Alagoas, Maceió, Brazil., Freitas MEG; Department of Pharmaceutical Sciences, Federal University of Paraíba, João Pessoa, Brazil., Zhan P; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China., Green KD; Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, 40536-0596, United States., Garneau-Tsodikova S; Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, 40536-0596, United States., Mendonça-Júnior FJB; Post-Graduation Program in Natural Products and Bioactive Synthetics, Federal University of Paraíba, João Pessoa, Brazil., Rodrigues-Junior VS; Department of Pharmaceutical Sciences, Federal University of Paraíba, João Pessoa, Brazil; Post-Graduation Program in Natural Products and Bioactive Synthetics, Federal University of Paraíba, João Pessoa, Brazil., Silva-Júnior EFD; Research Group of Biological and Molecular Chemistry, Institute of Chemistry and Biotechnology, Federal University of Alagoas, Lourival Melo Mota Avenue, AC. Simões campus, 57072-970 Alagoas, Maceió, Brazil. Electronic address: edeildo.junior@iqb.ufal.br.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2024 Jun 15; Vol. 108, pp. 117774. Date of Electronic Publication: 2024 May 26.
DOI: 10.1016/j.bmc.2024.117774
Abstrakt: Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which remains a significant global health challenge. The emergence of multidrug-resistant (MDR) Mtb strains imposes the development of new therapeutic strategies. This study focuses on the identification and evaluation of potential inhibitors against Mtb H37Ra through a comprehensive screening of an in-house chemolibrary. Subsequently, a promising pyrimidine derivative (LQM495) was identified as promising and then further investigated by experimental and in silico approaches. In this context, computational techniques were used to elucidate the potential molecular target underlying the inhibitory action of LQM495. Then, a consensus reverse docking (CRD) protocol was used to investigate the interactions between this compound and several Mtb targets. Out of 98 Mtb targets investigated, the enhanced intracellular survival (Eis) protein emerged as a target for LQM495. To gain insights into the stability of the LQM495-Eis complex, molecular dynamics (MD) simulations were conducted over a 400 ns trajectory. Further insights into its binding modes within the Eis binding site were obtained through a Quantum mechanics (QM) approach, using density functional theory (DFT), with B3LYP/D3 basis set. These calculations shed light on the electronic properties and reactivity of LQM495. Subsequently, inhibition assays and kinetic studies of the Eis activity were used to investigate the activity of LQM495. Then, an IC 50 value of 11.0 ± 1.4 µM was found for LQM495 upon Eis protein. Additionally, its V max , K m , and K i parameters indicated that it is a competitive inhibitor. Lastly, this study presents LQM495 as a promising inhibitor of Mtb Eis protein, which could be further explored for developing novel anti-TB drugs in the future.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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