ABSTRACT
In the present study, we attempted to develop a novel class of compounds active against Pseudomonas aeruginosa (Pa) by exploring the pharmaceutically well exploited enzyme targets. Since, lack of Pa gyrase B crystal structures, Thermus thermophilus gyrase B in complex with novobiocin (1KIJ) was used as template to generate model structure by performing homology modeling. Further the best model was validated and used for high-throughput virtual screening, docking and dynamics simulations using the in-house database for identification of Pa DNA gyrase B inhibitors. This study led to an identification of three lead molecules with IC50 values in range of 6.25-15.6 µM against Pa gyrase supercoiling assay. Lead-1 optimization and expansion resulted in 15 compounds. Among the synthesized compounds six compounds were shown good enzyme inhibition than Lead-1 (IC50 6.25 µM). Compound 13 emerged as the most potential compound exhibiting inhibition of Pa gyrase supercoiling with an IC50 of 2.2 µM; and in-vitro Pa activity with MIC of 8 µg/mL in presence of efflux pump inhibitor; hence could be further developed as novel inhibitor for Pa gyrase B.
Subject(s)
Bacterial Proteins/metabolism , DNA Gyrase/metabolism , Pseudomonas aeruginosa/enzymology , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , DNA Gyrase/chemistry , Drug Design , Humans , Models, Molecular , Oxazoles/chemical synthesis , Oxazoles/chemistry , Oxazoles/pharmacology , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/drug effects , Thiazoles/chemical synthesis , Thiazoles/chemistry , Thiazoles/pharmacology , Topoisomerase II Inhibitors/chemical synthesisABSTRACT
Pantothenate synthetase (PS) enzyme involved in the pantothenate biosynthetic pathway is essential for the virulence and persistent growth of Mycobacterium tuberculosis (MTB). It is encoded by the panC gene, and has become an appropriate target for developing new therapeutics for tuberculosis. Here we report new inhibitors active against MTB PS developed using energy based pharmacophore modelling of the available proteininhibitor complex (3IVX) and virtual screening of a large commercial library. The e-pharmacophore model consisted of a ring aromatic (R), negative ionizable (N) and acceptor (A) sites. Compounds 5 and 10 emerged as promising hits with IC50 s 2.18â µM and 6.63â µM respectively. Further structural optimization was attempted to optimize leadâ 10 using medicinal chemistry approach and six compounds were found to exhibit better enzyme inhibition compared to parent compound leadâ 10 (<6â µM).