title: Binding affinity models for Falcipain inhibition based on the Linear Interaction Energy method.
abstract: The high rate of drug resistance as well as the complex biochemical process of the parasite reproduction cycle makes development of new drugs for malaria a very important but challenging task. Falcipain 2 (FL2) and Falcipain 3 (FL3) are the major cysteine protease enzymes that play a central role in providing essential amino acids for the parasite's protein biosynthesis through the hemoglobin hydrolysis process. Selective inhibition of these enzymes is considered as a promising chemotherapeutic target. In the present investigation, the highly efficient linear interaction energy (LIE) method has been parameterized for binding affinity predictions and assessed with a set of 244 compounds for FL2 and FL3 inhibition. The results revealed that the van der Waals energy is very important for ligands binding to Falcipain proteins and that, overall, the electrostatic energy contribution is minor. The best models obtained for FL2 and FL3 give root mean square errors (RMSE) of 1.82 and 1.33kcal/mol respectively, for the test set. In this study, we also investigate how the choice of initial protein-ligand confirmation (pose) impacts the overall quality of the LIE models. Moreover, the transferability of LIE parameters is further discussed.
authors: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark.
authors: Vasanthanathan
authors: V
authors: Poongavanam
authors: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark. Electronic address: kongsted@sdu.dk.
authors: Jacob
authors: J
authors: Kongsted
mesh_terms: D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D018499:Linear Energy Transfer; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015999:Multivariate Analysis; D025341:Principal Component Analysis; D011743:Pyrimidines / Q000737:chemistry; D015203:Reproducibility of Results; D013816:Thermodynamics
chemical_list: D008024:Ligands; D011743:Pyrimidines; D003546:Cysteine Endopeptidases; C099607:falcipain; C416224:falcipain 2; C443101:falcipain 3
keywords: Binding affinity prediction; Falcipain 2; Falcipain 3; Glide; LIE; Malaria; QPLD