Species Phytoconstituents as Potential Lead Compounds against Carbapenemase: A Computational Approach.

The evolution of antibiotic-resistant carbapenemase has negatively impacted the management of critical healthcare-associated infections. carbapenemase-2- (KPC-2-) expressing bacteria have developed resistance to conventional therapeutic options, including those used as a last resort for life-threatening diseases. In this study, species phytoconstituents were screened for their potential to inhibit KPC-2 protein using approaches. Molecular docking was used to identify strong KPC-2 protein binding phytoconstituents retrieved from the literature. The best-docked conformation of the ligands was selected based on their glide energy and binding interactions. To determine their binding free energies, these hit compounds were subjected to molecular mechanics with generalized born and surface area (MM-GBSA) in the PRIME module. Pharmacological assessments of the ligands were performed to evaluate their drug-likeness. Molecular dynamic (MD) simulations were used to analyze the conformational stability of the selected druglike compounds within the active site of the KPC-2 protein. Overall, a total of 69 phytoconstituents were compiled from the literature. Fourteen of these compounds exhibited a stronger binding affinity for the protein target than the reference drugs. Four of these top hit compounds, DB09, DB12, DB28, and DB66, revealed the highest efficacy in terms of drug-likeness properties. The MD simulation established that among the druglike compounds, DB66 attained stable conformations after 150 ns simulation in the active site of the protein. We concluded that DB66 from species could play a significant role in therapeutic efforts against KPC-2-expressing bacteria.