<i>In silico</i>
            studies of alkaloids and their derivatives against N-acetyltransferase EIS protein from
            <i>Mycobacterium tuberculosis</i>

Swain, Supriya P.; Ahamad, Shahzaib; Samarth, Nikhil; Singh, Shailza; Gupta, Dinesh; Kumar, Shailesh

doi:10.1080/07391102.2023.2259487

Cited by 4 publications

(2 citation statements)

References 80 publications

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“…The Chimera application and Biovia Discovery Studio 2021 used to create this artwork. The molecular docking poses provided insights into the interaction between the drug and each target protein, highlighting the bonding strength of the reported ligand with these proteins ( 47 , 48 ). It has been seen that the complex 03 has formed total five bonds where three are hydrogen bonds (THR C: 240, and ASP C: 238), and the complex 29 has documented total including HIS C: 205 (Hydrogen bonds), and the others two are ASP C: 219, and VAL C: 236.…”

Section: Results Analysismentioning

confidence: 99%

In silico evaluation of anti-colorectal cancer inhibitors by Resveratrol derivatives targeting Armadillo repeats domain of APC: molecular docking and molecular dynamics simulation

Akash,

Islam,

Bhuiyan

et al. 2024

Front. Oncol.

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Colorectal cancer is the second leading cause of cancer-related deaths. In 2018, there were an estimated 1.8 million cases, and this number is expected to increase to 2.2 million by 2030. Despite its prevalence, the current therapeutic option has a lot of side effects and limitations. Therefore, this study was designed to employ a computational approach for the identification of anti-cancer inhibitors against colorectal cancer using Resveratrol derivatives. Initially, the pass prediction spectrum of 50 derivatives was conducted and selected top seven compounds based on the maximum pass prediction score. After that, a comprehensive analysis, including Lipinski Rule, pharmacokinetics, ADMET profile study, molecular orbitals analysis, molecular docking, molecular dynamic simulations, and MM-PBSA binding free energy calculations. The reported binding affinity ranges of Resveratrol derivatives from molecular docking were -6.1 kcal/mol to -7.9 kcal/mol against the targeted receptor of human armadillo repeats domain of adenomatous polyposis coli (APC) (PDB ID: 3NMW). Specifically, our findings reported that two compounds [(03) Resveratrol 3-beta-mono-D-glucoside, and (29) Resveratrol 3-Glucoside] displayed the highest level of effectiveness compared to all other derivatives (-7.7 kcal/mol and -7.9 kcal/mol), and favorable drug-likeness, and exceptional safety profiles. Importantly, almost all the molecules were reported as free from toxic effects. Subsequently, molecular dynamic simulations conducted over 100ns confirmed the stability of the top two ligand-protein complexes. These findings suggest that Resveratrol derivatives may be effective drug candidate to manage the colorectal cancer. However, further experimental research, such as in vitro/in vivo studies, is essential to validate these computational findings and confirm their practical value.

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Section: Results Analysismentioning

confidence: 99%

In silico evaluation of anti-colorectal cancer inhibitors by Resveratrol derivatives targeting Armadillo repeats domain of APC: molecular docking and molecular dynamics simulation

Akash,

Islam,

Bhuiyan

et al. 2024

Front. Oncol.

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“…Mutations that lead to eis overexpression naturally occur in clinical isolates of M. tuberculosis, leading to kanamycin resistance (28,(66)(67)(68)(69)(70)(71). Numerous studies have reported inhibitors of Eis as a potential path to prevent aminoglycoside resistance during M. tuberculosis infection (81)(82)(83)(84)(85)(86)(87)(88)(89)(90). Eis reversibly acetylates lysine residues in the HupB protein, affecting chromosomal condensation in M. tuberculosis (26).…”

Section: Discussionmentioning

confidence: 99%

N-acetyl-transferases required for iron uptake and aminoglycoside resistance promote virulence lipid production inM. marinum

Jones,

Pareek,

et al. 2024

Preprint

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Phagosomal lysis is a key aspect of mycobacterial infection of host macrophages. Acetylation is a protein modification mediated enzymatically by N-acetyltransferases (NATs) that impacts bacterial pathogenesis and physiology. To identify NATs required for lytic activity, we leveragedMycobacterium marinum,a nontubercular pathogen and an established model forM. tuberculosis. M. marinumhemolysis is a proxy for phagolytic activity. We generatedM. marinumstrains with deletions in conserved NAT genes and screened for hemolytic activity. Several conserved lysine acetyltransferases (KATs) contributed to hemolysis. Hemolysis is mediated by the ESX-1 secretion system and by phthiocerol dimycocerosate (PDIM), a virulence lipid. For several strains, the hemolytic activity was restored by the addition of second copy of the ESX-1 locus. Using thin-layer chromatography (TLC), we found a single NAT required for PDIM and phenolic glycolipid (PGL) production. MbtK is a conserved KAT required for mycobactin siderophore synthesis and virulence. Mycobactin J exogenously complemented PDIM/PGL production in the ΔmbtKstrain. The ΔmbtK M. marinumstrain was attenuated in macrophage andGalleria mellonellainfection models. Constitutive expression of eithereisorpapA5,which encode a KAT required for aminoglycoside resistance and a PDIM/PGL biosynthetic enzyme, rescued PDIM/PGL production and virulence of the ΔmbtKstrain. Eis N-terminally acetylated PapA5in vitro, supporting a mechanism for restored lipid production. Overall, our study establishes connections between the MbtK and Eis NATs, and between iron uptake and PDIM and PGL synthesis inM. marinum. Our findings underscore the multifunctional nature of mycobacterial NATs and their connection to key virulence pathways.Significance StatementAcetylation is a modification of protein N-termini, lysine residues, antibiotics and lipids. Many of the enzymes that promote acetylation belong to the GNAT family of proteins.M. marinumis a well-established as a model to understand howM. tuberculosiscauses tuberculosis. In this study we sought to identify conserved GNAT proteins required for early stages of mycobacterial infection. UsingM. marinum,we determined that several GNAT proteins are required for the lytic activity ofM. marinum.We uncovered previously unknown connections between acetyl-transferases required for iron uptake and antimicrobial resistance, and the production of the unique mycobacterial lipids, PDIM and PGLOur data support that acetyl-transferases from the GNAT family are interconnected, and have activities beyond those previously reported.

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Suppressing Mycobacterium tuberculosis virulence and drug resistance by targeting Eis protein through computational drug discovery

Kumar,

Sahoo,

Ranjan

et al. 2024

Mol Divers

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In silico studies of alkaloids and their derivatives against N-acetyltransferase EIS protein from Mycobacterium tuberculosis

Cited by 4 publications

References 80 publications

In silico evaluation of anti-colorectal cancer inhibitors by Resveratrol derivatives targeting Armadillo repeats domain of APC: molecular docking and molecular dynamics simulation

In silico evaluation of anti-colorectal cancer inhibitors by Resveratrol derivatives targeting Armadillo repeats domain of APC: molecular docking and molecular dynamics simulation

N-acetyl-transferases required for iron uptake and aminoglycoside resistance promote virulence lipid production inM. marinum

Suppressing Mycobacterium tuberculosis virulence and drug resistance by targeting Eis protein through computational drug discovery

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