Computational Insights into the Binding Potential of Natural Products Against Pseudomonas aeruginosa Metallo-beta-lactamase VIM-1 to Combat Antibiotic Resistance.

Abstract

Metallo-beta-lactamase VIM-1 is a key factor contributing to bacterial resistance against beta-lactam antibiotics, including carbapenems, in Pseudomonas aeruginosa. The infections caused by the bacterium are associated with high morbidity and mortality, especially in immunocompromised patients that involve pathological conditions leading to hospitalization. Its capability to evade a wide range of antibiotics commonly used against the bacterium has been one of the strong survival features of the bacterium. With the increasing prevalence of antibiotic resistance mediated by VIM-1, the urgent need for novel inhibitors to treat such infections is underlined. This work employs a computational drug discovery approach to identify inhibitors against VIM-1 from the Molport library of natural compounds. Three promising compounds, ZINC000044404209, ZINC000038140885, and ZINC000037538575, based on high docking scores, had been selected from virtual screening using the Lipinski filter. Re-docking thus further validated their interactions with the active site of VIM-1. Molecular dynamics simulations of 300 ns obtained that ZINC000044404209 and ZINC000038140885 were more structurally stable than the control, evident from the lower values of root mean square deviation and root mean square fluctuation, with stable hydrogen bonding and compact radius of gyration values. Calculations of free binding energy by using the Molecular Mechanics Generalized Born Surface Area method finally confirmed that the compound ZINC000038140885 showed the most favorable binding energy of -108.13 kcal/mol, followed by the ZINC000044404209 showing -38.02 kcal/mol binding energy. Therefore, compounds with stronger binding and stability than the control were identified and might be potent inhibitors targeting VIM-1. The current in silico study has provided valuable lead compounds that may be further experimentally validated in developing new therapeutic strategies against antibiotic-resistant P. aeruginosa.