In silico design of potential drug leads against carbapenemase of carbapenem-resistant Klebsiella pneumoniae

Abstract

Carbapenem-resistant Enterobacteriaceae (CRE), including Klebsiella pneumoniae (CRKP), cause nosocomial infections like pneumonia and urinary tract infections (UTIs). CREs are multi-drug resistant against so-called “last resort drugs” like carbapenem. The objective of this study is to find novel ligand structures in silico that can serve as potential drug leads against Klebsiella pneumonia Carbapenemase (KPC). Sequence alignment of KPC from Klebsiella and other related bacteria revealed a highly conserved active site and key residues involved in catalysis. The KPC enzyme was docked with 6,699 compounds derived from the Traditional Chinese Medical Systems Pharmacology database, and 58 top binders with binding energies from -9.3 kcal/mol were selected as templates for ligand design. Out of 428 total designs, design#1, design#2, design#3, design#4 and design#5 were chosen as the compounds for the next stage of optimization. These five passed all of Lipinski’s rules and had binding energies of at least -10.1 kcal/mol, indicating very strong affinity of the ligand to the enzyme. design#2 was chosen as the best candidate with the best drug-likeness among all of them since it passed the most number of parameters while also having the highest binding energy. When compared to commonly used drugs like ertapenem, aztreonam and meropenem, the designed ligands were better in terms of binding energy and other physicochemical properties (Lipinski’s Rule of Five).