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Lian, X.* ; Xia, Z. ; Li, X.* ; Karpov, P. ; Jin, H.* ; Tetko, I.V. ; Xia, J.* ; Wu, S.*

Anti-MRSA drug discovery by ligand-based virtual screening and biological evaluation.

Bioorg. Chem. 114:105042 (2021)
Postprint DOI PMC
Open Access Green
S. aureus resistant to methicillin (MRSA) is one of the most-concerned multidrug resistant bacteria, due to its role in life-threatening infections. There is an urgent need to develop new antibiotics against MRSA. In this study, we firstly compiled a data set of 2,3-diaminoquinoxalines by chemical synthesis and antibacterial screening against S. aureus, and then performed cheminformatics modeling and virtual screening. The compound with the Specs ID of AG-205/33156020 was discovered as a new antibacterial agent, and was further identified as a Gyrase B (GyrB) inhibitor. In light of the common features, we hypothesized that the 6c as the representative of 2,3-diaminoquinoxalines also inhibited GyrB and eventually proved it. Via molecular docking and molecular dynamics simulations, we identified binding modes of AG-205/33156020 and 6c to the ATPase domain of GyrB. Importantly, these GyrB inhibitors inhibited the MRSA strains and showed selectivity to HepG2 and HUVEC. Taken together, this research work provides an effective ligand-based computational workflow for scaffold hopping in anti-MRSA drug discovery, and discovers two new GyrB inhibitors that are worthy of further development.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Antibacterial Agent ; Antibiotic Resistance ; Dna Gyrase Inhibitors ; Mrsa ; Virtual Screening; Dna Gyrase; Antibiotics; Inhibitors
Language english
Publication Year 2021
HGF-reported in Year 2021
ISSN (print) / ISBN 0045-2068
e-ISSN 1090-2120
Journal Bioorganic chemistry
Quellenangaben Volume: 114, Issue: , Pages: , Article Number: 105042 Supplement: ,
Publisher Elsevier
Publishing Place San Diego, Calif.
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-503000-001
Grants China Scholarship Council (CSC)
PUMC Graduate Students Innovation Fund
CAMS Innovation Fund for Medical Sciences
DOI 10.1016/j.bioorg.2021.105042
WOS ID WOS:000689722000001
Scopus ID 85107693068
PubMed ID 34120024
Erfassungsdatum 2021-07-12
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