title: Structural features of falcipain-3 inhibitors: an in silico study.
abstract: Falcipain-3, the major cysteine hemoglobinase from the human malaria parasite Plasmodium falciparum, is critical for parasite development and is considered as a promising chemotherapeutic target. In order to understand the structure-activity correlation of falcipain-3 inhibitors, a set of ligand- and receptor-based 3D-QSAR models were developed in the present work employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) for 247 2-pyrimidinecarbonitrile derivatives. An optimum ligand-based CoMSIA model yielded a cross validation Q(2) = 0.501, non-cross validation Rncv(2) = 0.821 and predictive Rpred(2) = 0.750. In addition, docking analysis and molecular dynamics simulation were applied to elucidate the probable binding modes of the ligand in the falcipain-3 binding pocket. Graphic representation of the results, as contoured 3D coefficient plots, also provides a clue to the reasonable modification of molecules. (1) Bulky substituents at the 3-position, and rings B and D increase the biological activity; (2) electrostatic groups at rings B, C and D are likely helpful to increase the falcipain-3 inhibition; (3) hydrophobic groups at rings B and D are favored; (4) Gly92, Ile94 and Thr95 which formed several H-bonds and a water-bridged H-bond are crucial for falcipain-3 inhibitors. This model, we hope, will be of help in designing and predicting novel falcipain-3 inhibitors.
authors.affiliation: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), Dalian University of Technology, Dalian, Liaoning 116024, PR China. jhwang_dlut@163.com
authors.forename: Jinghui
authors.initials: J
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Yinfeng
authors.initials: Y
authors.lastname: Yang
authors.forename: Shuwei
authors.initials: S
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010963:Plasmodium falciparum / Q000201:enzymology; D025341:Principal Component Analysis; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
chemical_list: D015853:Cysteine Proteinase Inhibitors; D003546:Cysteine Endopeptidases; C443101:falcipain 3