title: Molecular docking and 3D-quantitative structure activity relationship analyses of peptidyl vinyl sulfones: Plasmodium Falciparum cysteine proteases inhibitors.
abstract: Comparative molecular field analysis (CoMFA) 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 CoMSIA 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.
authors.affiliation: Centro de Investigação em Química da Universidade do Porto, Departamento de Química, Portugal. ca.teixeira@ua.pt
authors.forename: Cátia
authors.initials: C
authors.lastname: Teixeira
authors.forename: José R B
authors.initials: JR
authors.lastname: Gomes
authors.forename: Thierry
authors.initials: T
authors.lastname: Couesnon
authors.forename: Paula
authors.initials: P
authors.lastname: Gomes
mesh_terms: D000495:Allosteric Site; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D057056:Cysteine Proteases / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D010963:Plasmodium falciparum; D017433:Protein Structure, Secondary; D021281:Quantitative Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D008024:Ligands; D013450:Sulfones; C009873:divinyl sulfone; D057056:Cysteine Proteases; D003546:Cysteine Endopeptidases; C416224:falcipain 2