Quantum Mechanics/Molecular Mechanics Optimizations of Zinc Metallo- β-Lactamase Inhibitor

Abstract

Metallo-β-lactamase (MBL) is a zinc-dependent enzyme that inactivates a wide range of β-lactam antibiotics. Currently, there is no FDA-approved inhibitor for overcoming MBL causing drug resistance. The Sham Lab has recently discovered analogs of 8-hydroxyquinoline (8HQ) as a low-cytotoxic, nanomolar MBL inhibitor against NDM-1 and VIM-2. The goal of the project is to apply the quantum mechanics/molecular mechanics (QM/MM) method to explore the effect of aromatic substitutions and electronic polarization on binding affinity. Additionally, in-silico combinatorial library design will afford a high throughput discovery platform to identify and optimize novel 8HQ for overcoming the antibiotic drug resistance effect of MBL