title: Comparative study between 3D-QSAR and Docking-Based Pharmacophore models for potent Plasomodium falciparum dihydroorotate dehydrogenase inhibitors.
abstract: Malaria, caused by infections of the human malaria parasites Plasmodium falciparum, is a global infectious parasitic disease. Each year, about three million people died from malaria and the majority of whom are pregnant women and young children. Recently, a number of research attempt to reduce malaria parasite resistance and the toxicity of anti-malarial drugs. Nowadays, Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was validated as a potent drug target to inhibit malarial activity by blocking pyrimidine biosynthesis. In this study, we employed 3D-QSAR Pharmacophore Generation and Docking-Based Pharmacophore Development to build the pharmacophore by using the collected 67 effective inhibitors against PfDHODH. 3D-QSAR Pharmacophore model, Hypo1, shows the high correlation coefficient (0.935), the lowest RMS deviation (2.15), the predicting accuracy of successful rates to training set (89.4%) and test set compounds (72.4%), respectively, revealing favorable predictive ability and is a reliable for further study. Additionally, Docking-Based Pharmacophore model, DBP-All255, exhibits comparable predictive capability to that of Hypo1, while DBP-Top1 shows poor statistical significance. This study reveals pharmacophore features of Hypo1, built by 3D-QSAR Pharmacophore Generation, are well-complementary to the functional residues in the active site of PfDHODH and is of great reliable for database screening.
authors.affiliation: National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 112, Taiwan.
authors.forename: Tien-Sheng
authors.initials: TS
authors.lastname: Tseng
authors.affiliation: The Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan; The Ph.D. Program for Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Institute of Biotechnology, National Changhua University of Education, Changhua, Taiwan.
authors.forename: Nai-Wan
authors.initials: NW
authors.lastname: Hsiao
authors.affiliation: Joint Biobank, Office of Human Research, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Yun-Ru
authors.initials: YR
authors.lastname: Liu
authors.affiliation: National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 112, Taiwan; The Ph.D. Program for Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan. Electronic address: tkc@nricm.edu.tw.
authors.forename: Keng-Chang
authors.initials: KC
authors.lastname: Tsai
mesh_terms: D000962:Antimalarials / Q000737:chemistry*; D001555:Benzene Derivatives / Q000737:chemistry*; D000090722:Dihydroorotate Dehydrogenase; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010963:Plasmodium falciparum / Q000201:enzymology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D001555:Benzene Derivatives; D000090722:Dihydroorotate Dehydrogenase; D006571:Heterocyclic Compounds; D008024:Ligands; D044925:Oxidoreductases Acting on CH-CH Group Donors
keywords: 3D-QSAR Pharmacophore Generation; Catalyst; Docking-Based Pharmacophore Development; PfDHODH inhibitor; Pharmacophore