Discovery of phyto-compounds as novel inhibitors against NDM-1 and VIM-1 protein through virtual screening and molecular modelling

Amid the rise of multi-drug resistance among bacterial pathogens, the drying of the development pipeline of new antibiotics is worrisome. In search of new effective alternatives, phytocompounds can be considered a good one because of their immense antimicrobial property, low toxicity and huge structural diversity. In the present study, 200 phytocompounds were targeted against two Metallo beta-lactamase (MBL) enzymes (NDM-1 and VIM-1) through molecular docking and meropenem was used as a reference drug. The phytocompounds with docking score <=-8.0 kcal/mol were screened for their pharmacokinetic properties. The three best selected phytocompounds are Coriandrinonediol, Oleanderolide and Uzarigenin. Molecular docking helps to understand binding affinity. The selected phytocompounds showed better result than meropenem. Molecular interaction study reveals their competitive mechanism of inhibition against the target proteins. Coriandrinonediol has docking score -8.3 kcal/mol (NDM-1) and -8.9 kcal/mol (VIM-1), and oleanderolide has docking score -8.2 kcal/mol (NDM-1) and -9.3 kcal/mol (VIM-1). Uzarigenin has the highest binding affinity (-10.4 kcal/mol) among the three against VIM-1 and the lowest binding affinity (-8.1 kcal/mol) against NDM-1. Molecular dynamic (MD) simulation study also supports the stability and flexibility of the above phytocompounds during the MD run. Among the abovementioned three phytocompounds, oleanderolide has given the best result against both target proteins. These phytocompounds are first time reported as MBL inhibitors and their promising in silico results encourage to promote them for further investigation for in vitro and in vivo clinical trials. Communicated by Ramaswamy H. Sarma

Automated summary

Amid the rise of multi-drug resistance, finding new antibiotics is challenging. This study utilized molecular docking to screen and identify three phytocompounds with potential antimicrobial activity, outperforming the reference drug meropenem. The compounds showed competitive inhibition against the target proteins and demonstrated stability through molecular dynamics simulations. These findings suggest that the phytocompounds have potential as Metallo beta-lactamase inhibitors and warrant further in vitro and in vivo clinical trials.