title: QSAR study on the antimalarial activity of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors.
abstract: Plasmodium falciparum, the most fatal parasite that causes malaria, is responsible for over one million deaths per year. P. falciparum dihydroorotate dehydrogenase (PfDHODH) has been validated as a promising drug development target for antimalarial therapy since it catalyzes the rate-limiting step for DNA and RNA biosynthesis. In this study, we investigated the quantitative structure-activity relationships (QSAR) of the antimalarial activity of PfDHODH inhibitors by generating four computational models using a multilinear regression (MLR) and a support vector machine (SVM) based on a dataset of 255 PfDHODH inhibitors. All the models display good prediction quality with a leave-one-out q(2) >0.66, a correlation coefficient (r) >0.85 on both training sets and test sets, and a mean square error (MSE) <0.32 on training sets and <0.37 on test sets, respectively. The study indicated that the hydrogen bonding ability, atom polarizabilities and ring complexity are predominant factors for inhibitors' antimalarial activity. The models are capable of predicting inhibitors' antimalarial activity and the molecular descriptors for building the models could be helpful in the development of new antimalarial drugs.
authors.affiliation: a State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering , Beijing University of Chemical Technology , Beijing , P.R. China.
authors.forename: X
authors.initials: X
authors.lastname: Hou
authors.affiliation: a State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering , Beijing University of Chemical Technology , Beijing , P.R. China.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: a State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering , Beijing University of Chemical Technology , Beijing , P.R. China.
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.affiliation: a State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering , Beijing University of Chemical Technology , Beijing , P.R. China.|b Stake Key Laboratory of Natural and Biomimetic Drugs , Peking University , Beijing , P.R. China.
authors.forename: A
authors.initials: A
authors.lastname: Yan
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006860:Hydrogen Bonding; D008024:Ligands; D016014:Linear Models; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D010963:Plasmodium falciparum / Q000187:drug effects*; D011743:Pyrimidines / Q000096:biosynthesis; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D060388:Support Vector Machine
chemical_list: D000962:Antimalarials; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D008024:Ligands; D011743:Pyrimidines; D044925:Oxidoreductases Acting on CH-CH Group Donors
keywords: Kohonen’s self-organizing map; Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH); Quantitative structure–activity relationships (QSAR); multilinear regression; support vector machine