Identification of potential inhibitors derived from Indole and Pyrazole against New Delhi metallo-β-lactamase-1...

Carbapenemes are most powerful antibiotics available for the treatment of bacterial infections. However, bacteria have evolved the enzyme carbapenemase, specifically the New Delhi metallo-β-lactamase (NDM-1), hydrolyses broad spectrum of β-lactam antibiotics, including carbapenems, the last line of defense against infections, thus raising a significant global health issue. Hence, NDM-1 is a promising drug target against antibiotic resistance. A structure-based in silico approach employed to identify potential inhibitors of NDM-1. Virtual screening of 13,526 antibacterial compounds yielded ten candidates with the most favorable binding affinities (- 9.50 to - 8.07 kcal/mol), outperforming the reference ligand 7UOX-Lig (- 5.81 kcal/mol). Molecular dynamics simulations confirmed the stable binding of compounds 11,871, 12,801, 13,206, and 12,498, further supported by favorable MM/GBSA binding free energy values and consistent interaction profiles. The favorable thermodynamic profiles suggest that these compounds are promising NDM-1 inhibitors. They serve as potential leads for further optimization and experimental validation in developing novel therapeutics against NDM-1-mediated antibiotic resistance. Further in vitro and biochemical studies are warranted to confirm their efficacy and specificity, emphasizing the critical role of NDM-1 as a key target in combating β-lactam resistance.

The online version contains supplementary material available at 10.1007/s40203-025-00534-y.