Discovery of dual inhibitors of KPC-3 and KPC-15 of Klebsiella pneumoniae – a ligand and structure based virtual screening study
ABSTRACTBackgroundDevelopment of carbapenem resistance against Klebsiella pneumoniae is a situation of grave concern and require urgent attention. Among the KPC produced by K. pneumoniae, KPC-3 and KPC-15 play a major role in development of resistance to carbapenems.Materials and methodsKPC-2 structure was taken and then mutated to obtain the structure of KPC-3 and KPC-15. The binding sites of KPC-3 and KPC-15 were predicted by the COACH server. Drug like ligands from ZINC were then screened by ligand-based drug screening (LBVS) by keeping Relebactam as template. The top 50,000 selected ligands were then screened by structure based virtual screening (SBVS) using idock. The consensus weighted rank was computed for identifying ligands with dual inhibitory property. Relebactum was kept as a comparator for SBVS and the similarity search was conducted between the identified top 3 ligands against Relebactam. The ADMET properties were explored using admetSAR.ResultsBased on consensus weighted ranks, top 3 ligands with dual inhibitory property are-ZINC76060350 (consensus weighted rank - 1.5), ZINC05528590 (2), ZINC72290395 (3.5). All the top 3 dual inhibitor have a good probability of passing through the blood brain barrier. The RDKit and Morgan fingerprint scores between Relebactam and top three ligands were 0.24, 0.22, 0.23 and 0.26, 0.19, 0.25 respectively (showing only 20% similarity). Therefore, the three identified ligands may independently be effective in inhibiting the activity of KPC-3 and KPC-15.ConclusionThe suggested ligands could be taken forward for the development of new drug against a multi-resistant-Klebsiella pneumoniae infections.