Rational design of the first difluorostatone-based PfSUB1 inhibitors

Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages

“…The lack of activity of compounds 3 and 4 (clioquinol) highlights the importance of the side chain attached to the hydroxamate moiety for a correct interaction with the enzyme binding site. To assess the binding mode of 1 c and to explain the SARs observed for the class of compounds described herein, we performed a computational analysis by applying a docking procedure . Given the characteristics of the cavity and the presence of a charged metal ion in the binding site, we used the QM‐polarized ligand docking (QPLD) protocol as detailed in the Experimental Section below.…”

Structural characterization of Giardia duodenalis thioredoxin reductase ( g TrxR) and computational analysis of its interaction with NBDHEX

“…The resulting model of gTrxR in complex with NADPH was submitted to a refinement protocol as previously reported by us [42][43][44][45][46] 3.6% in allowed region and 0% of residues in outlier region) of our gTrxR refined model sit in the allowed regions of Ramachandran Plot ( Figure S1). This value is higher than the cut-off value (96.1%) defined for the most reliable models [49,50].…”

Methods for the Synthesis of α,α‐Difluoroketones

“…Enzyme inhibitors which form covalent adducts at the active site through nucleophilic attack on a highly electrophilic carbonyl group are the second key mode of action through which difluorinated ketones operate. Difluorostatone 8 is an inhibitor of subtilisin‐like protease in the malaria parasite (Figure ) . It functions through attack of a serine hydroxyl residue at the active site onto the difluoroketone moiety in the inhibitor.…”