title: Bayesian models trained with HTS data for predicting β-haematin inhibition and in vitro antimalarial activity.
abstract: A large quantity of high throughput screening (HTS) data for antimalarial activity has become available in recent years. This includes both phenotypic and target-based activity. Realising the maximum value of these data remains a challenge. In this respect, methods that allow such data to be used for virtual screening maximise efficiency and reduce costs. In this study both in vitro antimalarial activity and inhibitory data for β-haematin formation, largely obtained from publically available sources, has been used to develop Bayesian models for inhibitors of β-haematin formation and in vitro antimalarial activity. These models were used to screen two in silico compound libraries. In the first, the 1510 U.S. Food and Drug Administration approved drugs available on PubChem were ranked from highest to lowest Bayesian score based on a training set of β-haematin inhibiting compounds active against Plasmodium falciparum that did not include any of the clinical antimalarials or close analogues. The six known clinical antimalarials that inhibit β-haematin formation were ranked in the top 2.1% of compounds. Furthermore, the in vitro antimalarial hit-rate for this prioritised set of compounds was found to be 81% in the case of the subset where activity data are available in PubChem. In the second, a library of about 5000 commercially available compounds (Aldrich(CPR)) was virtually screened for ability to inhibit β-haematin formation and then for in vitro antimalarial activity. A selection of 34 compounds was purchased and tested, of which 24 were predicted to be β-haematin inhibitors. The hit rate for inhibition of β-haematin formation was found to be 25% and a third of these were active against P. falciparum, corresponding to enrichments estimated at about 25- and 140-fold relative to random screening, respectively.
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Wicht
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; Division of Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Combrinck
authors.affiliation: Division of Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa. Electronic address: timothy.egan@uct.ac.za.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Egan
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D001499:Bayes Theorem; D062313:Databases, Pharmaceutical; D055808:Drug Discovery / Q000379:methods*; D006420:Hemeproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000069550:Machine Learning; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008954:Models, Biological; D021261:Parasitic Sensitivity Tests / Q000379:methods; D010963:Plasmodium falciparum / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D006420:Hemeproteins; D054852:Small Molecule Libraries; C020753:hemozoin
keywords: Antimalarial; Bayesian statistics; Haemozoin; In silico screening; Machine learning; Malaria; β-Haematin