RESUMO
Antibiotic resistance against Mycobacterium tuberculosis (M.tb.) has been a significant cause of death worldwide. The Enhanced intracellular survival (EIS) protein of the bacteria is an acetyltransferase that multiacetylates aminoglycoside antibiotics, preventing them from binding to the bacterial ribosome. To overcome the EIS-mediated antibiotics resistance of M.tb., we compiled 888 alkaloids and derivatives from five different databases and virtually screened them against the EIS receptor. The compound library was filtered down to 87 compounds, which underwent additional analysis and filtration. Moreover, the top 15 most prominent phytocompounds were obtained after the drug-likeness prediction and ADMET screening. Out of 15, nine compounds confirmed the maximum number of hydrogen bond interactions and reliable binding energies during molecular docking. Additionally, the Molecular dynamics (MD) simulation of nine compounds showed the three most stable complexes, further verified by re-docking with mutated protein. The density functional theory (DFT) calculation was performed to identify the HOMO-LUMO energy gaps of the selected three potential compounds. Finally, our selected top lead compounds i.e., Alkaloid AQC2 (PubChem85634496), Nobilisitine A (ChEbi68116), and N-methylcheilanthifoline (ChEbi140673) demonstrated more favourable outcomes when compared with reference compounds (i.e., 39b and 2i) in all parameters used in this study. Therefore, we anticipate that our findings will help to explore and develop natural compound therapy against multi and extensively drug-resistant strains of M.tb.Communicated by Ramaswamy H. Sarma.
RESUMO
Over the years, Mycobacterium tuberculosis has been one of the major causes of death worldwide. As several clinical isolates of the bacteria have developed drug resistance against the target sites of the current therapeutic agents, the development of a novel drug is the pressing priority. According to recent studies on Mycobacterium tuberculosis, ATP binding sites of Mycobacterium tuberculosis serine/threonine protein kinases (MTPKs) have been identified as the new promising drug target. Among the several other protein kinases (PKs), Protein kinase G (PknG) was selected for the study because of its crucial role in modulating bacterium's metabolism to survive in host macrophages. In this work, we have focused on the H37Rv strain of Mycobacterium tuberculosis. A list of 477 flavanones obtained from the PubChem database was docked one by one against the crystallized and refined structure of PknG by in-silico techniques. Initially, potential inhibitors were narrowed down by preliminary docking. Flavanones were then selected using binding energies ranging from -7.9 kcal.mol-1 to -10.8 kcal.mol-1. This was followed by drug-likeness prediction, redocking analysis, and molecular dynamics simulations. Here, we have used experimentally confirmed drug AX20017 as a reference to determine candidate compounds that can act as potential inhibitors for PknG. PubChem165506, PubChem242065, PubChem688859, PubChem101367767, PubChem3534982, and PubChem42607933 were identified as possible target site inhibitors for PknG with a desirable negative binding energy of -8.1, -8.3, -8.4, -8.8, -8.6 and -7.9 kcal.mol-1 respectively. Communicated by Ramaswamy H. Sarma.
