Vinyl Sulfones as Antiparasitic Agents and a Structural Basis for Drug Design

Abstract

Cysteine proteases of the papain superfamily are implicated in a number of cellular processes and are important virulence factors in the pathogenesis of parasitic disease. These enzymes have therefore emerged as promising targets for antiparasitic drugs. We report the crystal structures of three major parasite cysteine proteases, cruzain, falcipain-3, and the first reported structure of rhodesain, in complex with a class of potent, small molecule, cysteine protease inhibitors, the vinyl sulfones. These data, in conjunction with comparative inhibition kinetics, provide insight into the molecular mechanisms that drive cysteine protease inhibition by vinyl sulfones, the binding specificity of these important proteases and the potential of vinyl sulfones as antiparasitic drugs.

Molecular docking and 3D-quantitative structure activity relationship analyses of peptidyl vinyl sulfones: Plasmodium Falciparum cysteine proteases inhibitors

“…This situation is analogous to that observed for the X-ray structure of rhodesain with the same ligand when compared with that of FP3 [24]. The authors attributed this event to the substitution of Ala166 in FP3 for the slightly bulky Met145 in rhodesain, which prevent the phenyl sulfone substituent from lying flat.…”

“…Based on these results, we infer that sulfonamides flexibility at R 1 0 position may be due to a similar flipping phenomenon. However, we reinforce that this flipping may be transient like the one observed for the complex of rhodesain with a vinyl sulfone where the R 1 0 moiety was modeled at half occupancy in both the ''flip in'' and ''flip out'' conformations [24]. Since the sulfonamides have more degrees of freedom and hence higher flexibility, it is likely that these compounds have higher occupancy in the ''flip in'' conformation than sulfones.…”

“…5). However, we believe that this flipping may be transient, like for the complex of rhodesain and a vinyl sulfone where the P1 0 moiety was modeled at half occupancy in both the ''in'' and ''out'' conformations [24].…”

“…Previously, the docking protocol was tested to verify if GOLD was able to reproduce the experimental data. For this validation, we selected the available complex of FP3 with K11017 inhibitor from the PDB databank (PDB code: 3BWK) [24]. The selection of FP3 structure (PDB code: 3BWK) to establish a docking protocol was based on the following reasons: (i) FP2 and FP3 are both cysteine proteases of Plasmodium Falciparum and contribute more or less equally to the digestion of hemoglobin in the food vacuole [21]; (ii) the superimposition of FP2 (3BPF, chainB) and FP3 (3BWK, chainA) using DaliLite server [25], matches 240 a-carbons with an RMSD of 1.1 Å , a Z score of 38.9 and a sequence of identity of 66% and (iii) FP3 X-ray structure (3BWK) give us access to the bioactive conformation of one of the peptidyl vinyl sulfones derivatives of this study (ligand 14).…”

Novel cinnamic acid/4-aminoquinoline conjugates bearing non-proteinogenic amino acids: Towards the development of potential dual action antimalarials

“…Cinnamic acid derivatives, due to their a,b-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation [9,16,17]. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers ( Fig.…”