Anti-MRSA drug discovery by ligand-based virtual screening and biological evaluation.
Bioorg Chem
; 114: 105042, 2021 09.
Article
in En
| MEDLINE
| ID: mdl-34120024
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Quinoxalines
/
Methicillin-Resistant Staphylococcus aureus
/
Anti-Bacterial Agents
Type of study:
Diagnostic_studies
/
Screening_studies
Limits:
Humans
Language:
En
Journal:
Bioorg Chem
Year:
2021
Document type:
Article
Affiliation country:
China