A novel potent metal-binding NDM-1 inhibitor was identified by fragment virtual, SPR and NMR screening.

ID: ALA4622835

Journal: Bioorg Med Chem

Title: A novel potent metal-binding NDM-1 inhibitor was identified by fragment virtual, SPR and NMR screening.

Authors: Guo H, Cheng K, Gao Y, Bai W, Wu C, He W, Li C, Li Z.

Abstract: NDM-1 can hydrolyze nearly all available β-lactam antibiotics, including carbapenems. NDM-1 producing bacterial strains are worldwide threats. It is still very challenging to find a potent NDM-1 inhibitor for clinical use. In our study, we used a metal-binding pharmacophore (MBP) enriched virtual fragment library to screen NDM-1 hits. SPR screening helped to verify the MBP virtual hits and identified a new NDM-1 binder and weak inhibitor A1. A solution NMR study of ¹⁵N-labeled NDM-1 showed that A1 disturbed all three residues coordinating the second zinc ion (Zn2) in the active pocket of NDM-1. The perturbation only happened in the presence of zinc ion, indicating that A1 bound to Zn2. Based on the scaffold of A1, we designed and synthesized a series of NDM-1 inhibitors. Several compounds showed synergistic antibacterial activity with meropenem against NDM-1 producing K. pneumoniae.

CiteXplore: 32229085

DOI: 10.1016/j.bmc.2020.115437

Patent ID: ┄