A novel potent metal-binding NDM-1 inhibitor was identified by fragment virtual, SPR and NMR screening. Issue 9 (1st May 2020)

• Record Type: Journal Article
• Authors: Guo, Huifang; Cheng, Kai; Gao, Yan; Bai, Weiqi; Wu, Cai; He, Wei; Li, Conggang; Li, Zhuorong
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 9(2020)
• Publication Date: 2020-05-01
• Subjects: NDM-1 -- Metal-binding pharmacophore -- Fragment-based drug design -- SPR -- NMR; NDM-1 New Delhi Metallo-1 -- SPR surface plasmon resonance -- NMR nuclear magnetic resonance -- MBP metal-binding pharmacophore -- MBL metallo-β-lactamase -- FBDD fragment-based drug discovery -- PDB Protein Data Bank -- CNCL PKU Chinese National Compound Library of Peking University -- LE ligand efficiency -- Hepes 2-(4-(2-hydroxyethyl)-1-piperazinyl)-ethansulfonic acid -- RU response unit -- DMSO dimethyl sulfoxide; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115437
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: A novel scaffold of NDM-1 inhibitors is described. The scaffold was discovered from metal-binding pharmacophore enriched library with virtual and SPR screen. Solution NMR found that the scaffold binds to the NDM-1 active pocket and the zinc ion in the pocket. Design and syntheses found compounds with synergistic antibacterial activity. 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 15 N-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 .