Prediction model for anti-malarial activities of hemozoin inhibitors using physicochemical properties [PublishAheadOfPrint]

The rapid spread of strains of malaria parasites resistant to several drugs has threatened global malaria control. Hence, the aim of this study was to predict the anti-malarial activity of chemical compounds possessing anti-hemozoin formation activity as a new means of anti-malarial drug discovery. After the initial in vitro anti-hemozoin formation high-throughput screening (HTS) of 9,600 compounds, a total of 224 hit compounds were identified as hemozoin inhibitors. These 224 compounds were tested for in vitro erythrocytic anti-malarial activity at 10 μM using the chloroquine-mefloquine sensitive Plasmodium falciparum strain, 3D7A. Two independent experiments were conducted. The physicochemical properties of the active compounds were extracted from ChemSpider and SciFinder databases. We analyzed the extracted data using Bayesian model averaging (BMA). Our findings revealed that lower numbers of S atoms, lower values of log D pH 3, 4 and 5, and higher values of ACD log D pH 7.4 had a significant association with anti-malarial activity among compounds possessing anti-hemozoin formation activity. The BMA model revealed an accuracy of 91.23%. We report new prediction models containing the physicochemical properties that shed light on effective chemical groups for synthetic anti-malarial compounds and help in silico screening for novel anti-malarial drugs.

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