Abstract
New Delhi metallo-beta-lactamase-1 (NDM-1), expressed in different Gram-negative bacteria, is a versatile enzyme capable of hydrolyzing beta-lactam rings containing antibiotics such as penicillins, cephalosporins, and even carbapenems. Multidrug resistance in bacteria mediated by NDM-1 is an emerging threat to the public health, with an enormous economic burden. There is a scarcity in the availability of specific NDM-1 inhibitors, and also a lag in the development of new inhibitors in pharmaceutical industries. In order to identify novel inhibitors of NDM-1, we screened a library of more than 20 million compounds, available at the MCULE purchasable database. Virtual screening led to the identification of six potential inhibitors, namely, MCULE-1996250788-0-2, MCULE-8777613195-0-12, MCULE-2896881895-0-14, MCULE-5843881524-0-3, MCULE-4937132985-0-1, and MCULE-7157846117-0-1. Furthermore, analyses by molecular docking and ADME properties showed that MCULE-8777613195-0-12 was the most suitable inhibitor against NDM-1. An analysis of the binding pose revealed that MCULE-8777613195-0-12 formed four hydrogen bonds with the catalytic residues of NDM-1 (His120, His122, His189, and Cys208) and interacted with other key residues. Molecular dynamics simulation and principal component analysis confirmed the stability of the NDM-1 and MCULE-8777613195-0-12 complex. The in vitro enzyme kinetics showed that the catalytic efficiency (i.e., k(cat)/K-m) of NDM-1 on various antibiotics decreased significantly in the presence of MCULE-8777613195-0-12, due to poor catalytic proficiency (k(cat)) and affinity (K-m). The IC50 value of MCULE-8777613195-0-12 (54.2 mu M) was comparable to that of a known inhibitor, i.e., D-captopril (10.3 p.M). In sum, MCULE-8777613195-0-12 may serve as a scaffold to further design/develop more potent inhibitors of NDM-1 and other beta-lactamases.