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

[Display omitted] 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 identi...

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Published in:	Bioorganic & medicinal chemistry Vol. 108; p. 117774
Main Authors:	Santos-Júnior, Paulo Fernando da Silva, Batista, Vitoria de Melo, Nascimento, Igor José dos Santos, Nunes, Isabelle Cavalcante, Silva, Leandro Rocha, Costa, Clara Andrezza Crisóstomo Bezerra, Freitas, Johnnatan Duarte de, Quintans-Júnior, Lucindo José, Araújo-Júnior, João Xavier de, Freitas, Maria Eugênia G. de, Zhan, Peng, Green, Keith D., Garneau-Tsodikova, Sylvie, Mendonça-Júnior, Francisco Jaime Bezerra, Rodrigues-Junior, Valnês S., Silva-Júnior, Edeildo Ferreira da
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 15-06-2024
Subjects:	Acetyltransferases - antagonists & inhibitors Acetyltransferases - metabolism Antitubercular Agents - chemistry Antitubercular Agents - pharmacology Bacterial Proteins - antagonists & inhibitors Bacterial Proteins - metabolism Dose-Response Relationship, Drug Eis Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Indole Microbial Sensitivity Tests Molecular Docking Simulation Molecular Dynamics Simulation Molecular Structure Mycobacterium tuberculosis Mycobacterium tuberculosis - drug effects Mycobacterium tuberculosis - enzymology Pyrimidine Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology Quinazoline Structure-Activity Relationship Quinazoline Mycobacterium tuberculosis QM Indole Eis Pyrimidine
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Summary:	[Display omitted] 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 IC50 value of 11.0 ± 1.4 µM was found for LQM495 upon Eis protein. Additionally, its Vmax, Km, and Ki 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0968-0896 1464-3391 1464-3391
DOI:	10.1016/j.bmc.2024.117774