IDENTIFYING POTENTIAL VIM-2 INHIBITORS: AN IN-SILICO APPROACH TO EXPLORE NOVEL SCAFFOLDS FOR ANTI MICROBIAL RESISTANCE

Abstract

Aim: This study aims to examine natural plant-based compounds known as flavonoids as potential inhibitors of VIM-2 Metallo-β-Lactamase (MBL) which is an enzyme produced by the dangerous bacteria Pseudomonas aeruginosa that makes it resistant to nearly all available antibiotics. One of the most pressing global health crises currently is antimicrobial resistance (AMR) and VIM-2 is a main driver of this resistance by breaking down β-lactam antibiotics which is the most widely used type of antibacterial drugs. There is an urgent need to find new and effective molecules that can block this enzyme as there is no clinically approved MBL inhibitor currently. Flavonoids are naturally occurring polyphenolic compounds which are found in large amount in plants. They were chosen as candidate molecules due to their known antibacterial properties and structural ability to interact with metal containing enzyme active sites. This study examines whether flavonoids can bind effectively to the active site of VIM-2 and potentially restore the effectiveness of β-lactam antibiotics using a computational in silico approach. A total of 30 flavonoids were initially considered and screened through ADME (Absorption, Distribution, Metabolism and Excretion) analysis for druglike properties and the best candidates underwent through molecular docking against the VIM-2 crystal structure (PDB ID: 4C1E) using AutoDock Vina. The popular thiol-based inhibitor D captopril was used as a reference compound for comparison.

Result: A total of 8 compounds successfully passed ADME and drug likeness filters like Lipinski's Rule of Five, PAINS and Brenk alerts and Ghose criteria from the 30 flavonoids selected initially and these were then taken for molecular docking. All 8 flavonoids showed stronger binding affinities than the reference inhibitor D-captopril (–6.20 kcal/mol) with binding energies ranging between –7.6 to –8.1 kcal/mol. Apigenin (PubChem CID: 5280443) showed highest binding affinity of –8.1 kcal/mol making it the best candidate among all. Interaction studies confirmed that the flavonoids formed stable forces with key enzymatic residues in the VIM-2 active site which includes ASP118, ASP117, HIS116, TRP87, PHE62 and ASN210. These residues are critical for zinc dependent β-lactam solvolysis. Other flavonoids including Apigenin and Genistein also showed direct interaction with the catalytic zinc ions (ZN501 and ZN502) which further supported their potential to disrupt enzyme activity.

Conclusion: Apigenin emerged as the most effective candidate among the eight flavonoids examined and displayed the strongest binding affinity and favorable interactions with the VIM 2 catalytic active site and surpassed the reference inhibitor D-captopril. These findings show that naturally occurring flavonoids hold significant promise as novel scaffold molecules for the development of MBL inhibitors. Their plant derived origin along with drug like pharmacokinetic properties and potent in silico binding profiles makes them highly attractive leads for combating antibiotic resistance. We strongly recommend validating these computational findings through molecular dynamics simulations, in vitro enzyme inhibition assays and ultimately in vivo experiments to confirm their therapeutic potential.