TY - JOUR
T1 - A consensus reverse docking approach for identification of a competitive inhibitor of acetyltransferase enhanced intracellular survival protein from Mycobacterium tuberculosis
AU - Santos-Júnior, Paulo Fernando da Silva
AU - Batista, Vitoria de Melo
AU - Nascimento, Igor José dos Santos
AU - Nunes, Isabelle Cavalcante
AU - Silva, Leandro Rocha
AU - Costa, Clara Andrezza Crisóstomo Bezerra
AU - de Freitas, Johnnatan Duarte
AU - Quintans-Júnior, Lucindo José
AU - de Araújo-Júnior, João Xavier
AU - de Freitas, Maria Eugênia G.
AU - Zhan, Peng
AU - Green, Keith D.
AU - Garneau-Tsodikova, Sylvie
AU - Mendonça-Júnior, Francisco Jaime Bezerra
AU - Rodrigues-Junior, Valnês S.
AU - Silva-Júnior, Edeildo Ferreira da
N1 - Publisher Copyright:
© 2024 Elsevier Ltd
PY - 2024/6/15
Y1 - 2024/6/15
N2 - 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.
AB - 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.
KW - Eis
KW - Indole
KW - Mycobacterium tuberculosis
KW - Pyrimidine
KW - QM
KW - Quinazoline
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UR - http://www.scopus.com/inward/citedby.url?scp=85194947327&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2024.117774
DO - 10.1016/j.bmc.2024.117774
M3 - Article
C2 - 38833750
AN - SCOPUS:85194947327
SN - 0968-0896
VL - 108
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
M1 - 117774
ER -