title: Discovery of novel antimalarial compounds enabled by QSAR-based virtual screening.
abstract: Quantitative structure-activity relationship (QSAR) models have been developed for a data set of 3133 compounds defined as either active or inactive against P. falciparum. Because the data set was strongly biased toward inactive compounds, different sampling approaches were employed to balance the ratio of actives versus inactives, and models were rigorously validated using both internal and external validation approaches. The balanced accuracy for assessing the antimalarial activities of 70 external compounds was between 87% and 100% depending on the approach used to balance the data set. Virtual screening of the ChemBridge database using QSAR models identified 176 putative antimalarial compounds that were submitted for experimental validation, along with 42 putative inactives as negative controls. Twenty five (14.2%) computational hits were found to have antimalarial activities with minimal cytotoxicity to mammalian cells, while all 42 putative inactives were confirmed experimentally. Structural inspection of confirmed active hits revealed novel chemical scaffolds, which could be employed as starting points to discover novel antimalarial agents.
authors.affiliation: The Laboratory for Molecular Modeling, Eshelman School of Pharmacy, CB# 7568, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Liying
authors.initials: L
authors.lastname: Zhang
authors.forename: Denis
authors.initials: D
authors.lastname: Fourches
authors.forename: Alexander
authors.initials: A
authors.lastname: Sedykh
authors.forename: Hao
authors.initials: H
authors.lastname: Zhu
authors.forename: Alexander
authors.initials: A
authors.lastname: Golbraikh
authors.forename: Sean
authors.initials: S
authors.lastname: Ekins
authors.forename: Julie
authors.initials: J
authors.lastname: Clark
authors.forename: Michele C
authors.initials: MC
authors.lastname: Connelly
authors.forename: Martina
authors.initials: M
authors.lastname: Sigal
authors.forename: Dena
authors.initials: D
authors.lastname: Hodges
authors.forename: Armand
authors.initials: A
authors.lastname: Guiguemde
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.forename: Alexander
authors.initials: A
authors.lastname: Tropsha
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008954:Models, Biological; D010963:Plasmodium falciparum / Q000187:drug effects*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000962:Antimalarials