title: High-Throughput Screening and Prediction Model Building for Novel Hemozoin Inhibitors Using Physicochemical Properties.
abstract: It is essential to continue the search for novel antimalarial drugs due to the current spread of resistance against artemisinin by Plasmodium falciparum parasites. In this study, we developed in silico models to predict hemozoin inhibitors as a potential first-step screening for novel antimalarials. An in vitro colorimetric high-throughput screening assay of hemozoin formation was used to identify hemozoin inhibitors from 9,600 structurally diverse compounds. The physicochemical properties of positive hits and randomly selected compounds were extracted from the ChemSpider database; they were used for developing prediction models to predict hemozoin inhibitors using two different approaches, i.e., traditional multivariate logistic regression and Bayesian model averaging. Our results showed that a total of 224 positive-hit compounds exhibited the ability to inhibit hemozoin formation, with 50% inhibitory concentrations (IC50s) ranging from 3.1 μM to 199.5 μM. The best model according to traditional multivariate logistic regression included the three variables octanol-water partition coefficient, number of hydrogen bond donors, and number of atoms of hydrogen, while the best model according to Bayesian model averaging included the three variables octanol-water partition coefficient, number of hydrogen bond donors, and index of refraction. Both models had a good discriminatory power, with area under the curve values of 0.736 and 0.781 for the traditional multivariate model and Bayesian model averaging, respectively. In conclusion, the prediction models can be a new, useful, and cost-effective approach for the first screen of hemozoin inhibition-based antimalarial drug discovery.
authors.affiliation: Department of Clinical Product Development, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Sakamoto, Nagasaki, Japan tienhuy@nagasaki-u.ac.jp hiraken@nagasaki-u.ac.jp.|Graduate School of Biomedical Sciences, Nagasaki University, Bunkyo-machi, Nagasaki, Japan.|Online Research Club, Nagasaki University, Sakamoto, Nagasaki, Japan.
authors.forename: Nguyen Tien
authors.initials: NT
authors.lastname: Huy
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University, Bunkyo-machi, Nagasaki, Japan.|Department of Immunogenetics, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Sakamoto, Nagasaki, Japan.
authors.forename: Pham Lan
authors.initials: PL
authors.lastname: Chi
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University, Bunkyo-machi, Nagasaki, Japan.|Department of Pharmacology and Therapeutic Innovation, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Nagai
authors.affiliation: University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam.|Department of Health Care Policy and Management, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Tran Ngoc
authors.initials: TN
authors.lastname: Dang
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University, Bunkyo-machi, Nagasaki, Japan.|Online Research Club, Nagasaki University, Sakamoto, Nagasaki, Japan.|Department of Immunogenetics, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Sakamoto, Nagasaki, Japan.
authors.forename: Evaristus Chibunna
authors.initials: EC
authors.lastname: Mbanefo
authors.affiliation: Faculty of Medicine, Al-Azhar University, Cairo, Egypt.
authors.forename: Ali Mahmoud
authors.initials: AM
authors.lastname: Ahmed
authors.affiliation: Online Research Club, Nagasaki University, Sakamoto, Nagasaki, Japan.|University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam.
authors.forename: Nguyen Phuoc
authors.initials: NP
authors.lastname: Long
authors.affiliation: Online Research Club, Nagasaki University, Sakamoto, Nagasaki, Japan.|University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam.
authors.forename: Le Thi Bich
authors.initials: LT
authors.lastname: Thoa
authors.affiliation: Online Research Club, Nagasaki University, Sakamoto, Nagasaki, Japan.|University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam.
authors.forename: Le Phi
authors.initials: LP
authors.lastname: Hung
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University, Bunkyo-machi, Nagasaki, Japan.|Department of Immunogenetics, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Sakamoto, Nagasaki, Japan.
authors.forename: Afaf
authors.initials: A
authors.lastname: Titouna
authors.affiliation: Department of Biomolecular Engineering, Kyoto Institute of Technology, Sakyo-ku, Kyoto, Japan.
authors.forename: Kaeko
authors.initials: K
authors.lastname: Kamei
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University, Bunkyo-machi, Nagasaki, Japan.|Department of Pharmacology and Therapeutic Innovation, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ueda
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University, Bunkyo-machi, Nagasaki, Japan tienhuy@nagasaki-u.ac.jp hiraken@nagasaki-u.ac.jp.|Department of Immunogenetics, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Sakamoto, Nagasaki, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hirayama
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D001499:Bayes Theorem; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006418:Heme / Q000737:chemistry; D006420:Hemeproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D057166:High-Throughput Screening Assays / Q000379:methods*; D016015:Logistic Models; D008962:Models, Theoretical; D010963:Plasmodium falciparum / Q000187:drug effects; D015203:Reproducibility of Results
chemical_list: D000962:Antimalarials; D006420:Hemeproteins; C020753:hemozoin; D006418:Heme
keywords: HTS; antimalarial; compounds; hematin; heme; hemozoin; in silico model; physical properties; screening