Structure–Kinetic Relationship Studies for the Development of Long Residence Time LpxC Inhibitors

Abstract

UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a promising drug target in Gram-negative bacteria. Previously, we described a correlation between the residence time of inhibitors on Pseudomonas aeruginosa LpxC (paLpxC) and the post-antibiotic effect (PAE) caused by the inhibitors on the growth of P. aeruginosa. Given that drugs with prolonged activity following compound removal may have advantages in dosing regimens, we have explored the structure–kinetic relationship for paLpxC inhibition by analogues of the pyridone methylsulfone PF5081090 (1) originally developed by Pfizer. Several analogues have longer residence times on paLpxC than 1 (41 min) including PT913, which has a residence time of 124 min. PT913 also has a PAE of 4 h, extending the original correlation observed between residence time and PAE. Collectively, the studies provide a platform for the rational modulation of paLpxC inhibitor residence time and the potential development of antibacterial agents that cause prolonged suppression of bacterial growth.

Determination of the Association between Mesotrione Sensitivity and Conformational Change of 4-Hydroxyphenylpyruvate Dioxygenase via Free-Energy Analyses

“…The dissociation rate of mesotrione from the Avena sativa HPPD (5.75 × 10 –6 s –1 ) was faster than that from the Arabidopsis thaliana (7.50 × 10 –4 s –1 ), suggesting that the dynamic behavior of H11 affected the dissociation rate of the inhibitor . Such difference in the dissociation rate of inhibitors might be due to the conformational change of protein, as reported in previous studies on several inhibitors, such as UDP-3- O -acyl- N -acetylglucosamine deacetylase, enoyl acyl carrier protein reductase, and human immunodeficiency virus type 1 (HIV-1) protease inhibitors. − Notably, a previous study reported that even a single residue mutation in HIV-1 protease alters the dynamic behavior of the flap and increases the dissociation rate of the inhibitor . Therefore, we suggest that the difference in the dynamic behavior of H11 between plants affected the dissociation rate of the inhibitor.…”

Predicting Protein–Ligand Binding and Unbinding Kinetics with Biased MD Simulations and Coarse-Graining of Dynamics: Current State and Challenges

“…Possibly, with the current rate of methodological improvements, our research community may reach this threshold in a few years. In the end, it might be that the insights the community gains from its research will be put to best use in the parametrization of structure–kinetics relationships ,− or machine-learning models ,,− that will provide a sufficiently fast estimate of unbinding and binding kinetics for computer-aided drug design.…”

Oxazolidinones as versatile scaffolds in medicinal chemistry

“…LpxC is a zinc metalloenzyme that plays an important role in the biosynthesis of lipid A, a glucosamine disaccharide that anchors lipopolysaccharide (LPS) to the outer membrane of Gram-negative bacteria. 71,72 Le et al working at Novartis identified by virtual screening an oxazolidine derivative with potent LpxC inhibitory activity ( K d = 0.065 nM). 73 Compound 45 (Fig.…”