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

Abstract

Comparative molecular field analysis (CoM-FA) and comparative molecular similarity indices analysis (CoMSIA) based on three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series (39 molecules) of peptidyl vinyl sulfone derivatives as potential Plasmodium Falciparum cysteine proteases inhibitors. Two different methods of alignment were employed: (i) a receptor-docked alignment derived from the structure-based docking algorithm GOLD and (ii) a ligand-based alignment using the structure of one of the ligands derived from a crystal structure from the PDB databank. The best predictions were obtained for the receptor-docked alignment with a CoMFA standard model (q 2 = 0.696 and r 2 = 0.980) and with CoMSIA combined electrostatic, and hydrophobic fields (q 2 = 0.711 and r 2 = 0.992). Both models were validated by a test set of nine compounds and gave satisfactory predictive r 2 pred values of 0.76 and 0.74, respectively. CoMFA and CoM-SIA contour maps were used to identify critical regions where any change in the steric, electrostatic, and hydrophobic fields may affect the inhibitory activity, and to highlight the key structural features required for biological activity. Moreover, the results obtained from 3D-QSAR analyses were superimposed on the Plasmodium Falciparum cysteine proteases active site and the main interactions were studied. The present work provides extremely useful guidelines for future structural modifications of this class of compounds towards the development of superior antimalarials.

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

“…S3). This suggests that the aryl substituent could be slightly bulky in depth but not in length, which matches the limitation of S2 cavity as already proposed by a previous study [37].…”

Analysis of non-peptidic compounds as potential malarial inhibitors against Plasmodial cysteine proteases via integrated virtual screening workflow

“…A 3D–QSAR study by Cátia et al ., on peptidyl vinyl sulfone derivatives as FP-2 inhibitors showed the major structural requirements necessary for optimal activity (Teixeira, Gomes, Couesnon, & Gomes, 2011). A similar approach on non-peptidic heteroarynitrile derivatives by Wang et al, led to comparable conclusions where different subsite pockets preferred groups with certain chemical properties (Wang et al, 2013).…”

Development of Plasmodium falciparum Protease Inhibitors in the Past Decade (2002–2012)

“…Finally, these authors also found a pattern of activity against the parasite cultures, depending on the substitution in the aryl ring of the vinyl sulfonate esters: presence of the electron-donating methoxy group led to an increase of activity over the unsubstituted ring, whereas the last one showed to be more active than the one bearing an electron-withdrawing fluorine [101]. More recently, a computational 3D-QSAR study on these three vinyl sulfone, sulfonamide and sulfonate ester families has identified critical regions where any change in the steric, electrostatic, and hydrophobic fields of the molecules may affect the inhibitory activity [102]. For instance, bulky groups at R 2 position (Fig.…”