Discovery of Baicalin as NDM-1 inhibitor: Virtual screening, biological evaluation and molecular simulation

Abstract

The emergence and worldwide spreads of carbapenemase producing bacteria, especially New Delhi metallo-β-lactamase (NDM-1), has made a great challenge to treat antibiotics-resistant bacterial infections. It can hydrolyse almost all β-lactam antibacterials. Unfortunately, there are no clinically useful inhibitors of NDM-1. In this study, structure-based virtual screening method led to the identification of Baicalin as a novel NDM-1 inhibitor. Inhibitory assays showed that Baicalin possessed a good inhibition of NDM-1 with IC₅₀ values of 3.89 ± 1.1 μM and restored the susceptibility of E.coli BL21(DE3)/pET28a-NDM-1 to clinically used β-lactam antibiotics. Molecular docking and molecular dynamics simulations obtained a complex structure between the relatively stable inhibitor molecule Baicalin and NDM-1 enzyme. The results showed that the carboxyl group in Baicalin directly interacted with the Zn²⁺ in the active center of the enzyme, and the residues such as Glu152, Gln123, Met67, Trp93 and Phe70 in the enzyme formed hydrogen bonds with Baicalin to further stabilize the complex structure.

Keywords: Molecular dynamics simulation; NDM-1 inhibitors; Natural products; Virtual screening.