Identification of Small Molecular Inhibitors for Efflux Protein: DrrA of Mycobacterium tuberculosis

Mustyala, Kiran Kumar; Malkhed, Vasavi; Chittireddy, Venkata Ramana Reddy; Vuruputuri, Uma

doi:10.1007/s12195-015-0427-2

Cited by 6 publications

(5 citation statements)

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“…Without heritability, IMM-driven phenotypic heterogeneity could still confer adaptive benefit through a ‘bet-hedging’ strategy ( Casadesús and Low, 2013 ; Wolf et al, 2005 ). This hypothesis is consistent with observations of M. tuberculosis ‘persister cells’ ( Vilchèze et al, 2017 ), minority groups that are pre-adapted to tolerate initial exposure to macrophage ( Daniel et al, 2011 ) and drug pressure ( Keren et al, 2011 ), by entering dormancy ( Jain et al, 2016 ) or activating efflux pumps ( Colangeli et al, 2005 ; Mustyala et al, 2016 ).…”

Section: Discussionsupporting

confidence: 90%

“…These include drug resistance, metal ion homeostasis ( corA ( Park et al, 2019 ), lpqS ( Darwin, 2015 ), mmpS4 ( Jones et al, 2014 ) , higA ( Schuessler et al, 2013 ) , mbtJ ( Chownk et al, 2018 ), and hemN McMahon et al, 2012 ), and the induction and maintenance of dormancy—all functions with examples of modulation by DNA adenine methylation in other human pathogens (Beaulaurier et al; Brunet et al, 2020 ; Cohen et al, 2016 ; Sánchez-Romero and Casadesús, 2020 ). The resistance-implicating genes among these mediate resistance through gene regulation ( whiB7 -controlled expression of eis, tap, and Rv1473 ( Duan et al, 2019 ; Morris et al, 2005 ), and raaS- controlled expression of Rv1218c and Rv1217c Wang et al, 2013 ), drug efflux ( drrA ( Mustyala et al, 2016 ) , iniA ( Colangeli et al, 2005 ), Rv3728 ( Gupta et al, 2010 ), and efflux-targets of whiB7 and raaS ), and other mechanisms ( glf ( Chen and Bishai, 1998 ) , mshC ( Parida et al, 2015 ) , mshD ( Vilchèze et al, 2008 ) , pafA ( Samanovic and Darwin, 2016 ), Rv3050c ( Nieto R et al, 2018 ), and gyrB ( Nosova et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

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Drivers and sites of diversity in the DNA adenine methylomes of 93 Mycobacterium tuberculosis complex clinical isolates

Modlin

Conkle-Gutierrez

Kim

et al. 2020

eLife

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This study assembles DNA adenine methylomes for 93 Mycobacterium tuberculosis complex (MTBC) isolates from seven lineages paired with fully-annotated, finished, de novo assembled genomes. Integrative analysis yielded four key results. First, methyltransferase allele-methylome mapping corrected methyltransferase variant effects previously obscured by reference-based variant calling. Second, heterogeneity analysis of partially active methyltransferase alleles revealed that intracellular stochastic methylation generates a mosaic of methylomes within isogenic cultures, which we formalize as ‘intercellular mosaic methylation’ (IMM). Mutation-driven IMM was nearly ubiquitous in the globally prominent Beijing sublineage. Third, promoter methylation is widespread and associated with differential expression in the ΔhsdM transcriptome, suggesting promoter HsdM-methylation directly influences transcription. Finally, comparative and functional analyses identified 351 sites hypervariable across isolates and numerous putative regulatory interactions. This multi-omic integration revealed features of methylomic variability in clinical isolates and provides a rational basis for hypothesizing the functions of DNA adenine methylation in MTBC physiology and adaptive evolution.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Drivers and sites of diversity in the DNA adenine methylomes of 93 Mycobacterium tuberculosis complex clinical isolates

Modlin

Conkle-Gutierrez

Kim

et al. 2020

eLife

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show abstract

“…2). Similar protocols were also reported earlier for the identification of the active site in the proteins [71][72][73][74]. …”

Section: Active Site Predictionsupporting

confidence: 55%

Targeting the ubiquitin-conjugating enzyme E2D4 for cancer drug discovery–a structure-based approach

et al. 2016

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Cancer progression is a global burden. The incidence and mortality now reach 30 million deaths per year. Several pathways of cancer are under investigation for the discovery of effective therapeutics. The present study highlights the structural details of the ubiquitin protein 'Ubiquitin-conjugating enzyme E2D4' (UBE2D4) for the novel lead structure identification in cancer drug discovery process. The evaluation of 3D structure of UBE2D4 was carried out using homology modelling techniques. The optimized structure was validated by standard computational protocols. The active site region of the UBE2D4 was identified using computational tools like CASTp, Q-site Finder and SiteMap. The hydrophobic pocket which is responsible for binding with its natural receptor ubiquitin ligase CHIP (C-terminal of Hsp 70 interacting protein) was identified through proteinprotein docking study. Corroborating the results obtained from active site prediction tools and protein-protein docking study, the domain of UBE2D4 which is responsible for cancer cell progression is sorted out for further docking study. Virtual screening with large structural database like CB_Div Set and Asinex BioDesign small molecular structural database was carried out. The obtained new ligand molecules that have shown affinity towards UBE2D4 were considered for ADME prediction studies. The identified new ligand molecules with acceptable parameters of docking, ADME are considered as potent UBE2D4 enzyme inhibitors for cancer therapy.

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“…, Mustyala et al. , and Ramatenki et al. for the identification of the template and the 3D model building.…”

Section: Resultsmentioning

confidence: 99%

Identification of small molecular inhibitors for efflux protein Rv2688c of Mycobacterium tuberculosis

Vadija

Mustyala

Malkhed

et al. 2018

Biotech and App Biochem

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Mycobacterium tuberculosis (Mtb) is the pathogen, which causes tuberculosis. The development of multidrug-resistant and extensively drug-resistant strains in Mtb is due to an efflux mechanism of antibiotics in the bacteria. The efflux pump proteins in the bacteria are implicated in the active efflux of antibiotics. The efflux pump protein, "fluoroquinolones export ATP-binding protein Rv2688c" (FEAB), is considered as a potential therapeutic target to prevent tuberculosis. In the present work, in silico protocols are applied to identify inhibitors for the FEAB protein to arrest the efflux mechanism. Comparative modeling techniques are used to build the protein structure. The generated structure consists of 9 helices, 13 beta strands, and 3 β sheets. The active site is predicted using active site prediction server tools. The virtual screening protocols are carried out to generate small ligand inhibitor structures. The identified ligand molecules show selective binding with Ser97, Glu99, Lys149, Asp171, Glu172, and Ser175 amino acid residues of the protein. The ligand molecules are subjected to in silico prediction of pharmaco kinetic properties, and the predicted IC (HERG) of all the molecules are less than -5.0, which is indicative of the identified ligand molecules is being potentially good FEAB inhibitors.

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Identification of Small Molecular Inhibitors for Efflux Protein: DrrA of Mycobacterium tuberculosis

Cited by 6 publications

References 50 publications

Drivers and sites of diversity in the DNA adenine methylomes of 93 Mycobacterium tuberculosis complex clinical isolates

Drivers and sites of diversity in the DNA adenine methylomes of 93 Mycobacterium tuberculosis complex clinical isolates

Targeting the ubiquitin-conjugating enzyme E2D4 for cancer drug discovery–a structure-based approach

Identification of small molecular inhibitors for efflux protein Rv2688c of Mycobacterium tuberculosis

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