Structural features of falcipain-3 inhibitors: an in silico study.

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.