| Title | Anti-MRSA drug discovery by ligand-based virtual screening and biological evaluation |
| Authors | Lian, Xu Xia, Zhonghua Li, Xueyao Karpov, Pavel Jin, Hongwei Tetko, Igor, V Xia, Jie Wu, Song |
| Affiliation | Chinese Acad Med Sci & Peking Union Med Coll, Dept New Drug Res & Dev, State Key Lab Bioact Subst & Funct Nat Med, Inst Mat Med, Beijing 100050, Peoples R China Helmholtz Zentrum Munchen, Res Ctr Environm Hlth GmbH, Inst Struct Biol, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany BIGCHEM GmbH, Valerystr 49, D-85716 Unterschleissheim, Germany Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China |
| Keywords | DNA GYRASE ANTIBIOTICS INHIBITORS |
| Issue Date | Sep-2021 |
| Publisher | BIOORGANIC CHEMISTRY |
| 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. |
| URI | http://hdl.handle.net/20.500.11897/624033 |
| ISSN | 0045-2068 |
| DOI | 10.1016/j.bioorg.2021.105042 |
| Indexed | SCI(E) |
| Appears in Collections: | 药学院 天然药物与仿生药物国家重点实验室 |
