Prioritization of anti-malarial hits from nature: chemo-informatic profiling of natural products with in vitro antiplasmodial activities and currently registered anti-malarial drugs

Abstract

BackgroundA large number of natural products have shown in vitro antiplasmodial activities. Early identification and prioritization of these natural products with potential for novel mechanism of action, desirable pharmacokinetics and likelihood for development into drugs is advantageous. Chemo-informatic profiling of these natural products were conducted and compared to currently registered anti-malarial drugs (CRAD).MethodsNatural products with in vitro antiplasmodial activities (NAA) were compiled from various sources. These natural products were sub-divided into four groups based on inhibitory concentration (IC50). Key molecular descriptors and physicochemical properties were computed for these compounds and analysis of variance used to assess statistical significance amongst the sets of compounds. Molecular similarity analysis, estimation of drug-likeness, in silico pharmacokinetic profiling, and exploration of structure–activity landscape were also carried out on these sets of compounds.ResultsA total of 1040 natural products were selected and a total of 13 molecular descriptors were analysed. Significant differences were observed among the sub-groups of NAA and CRAD for at least 11 of the molecular descriptors, including number of hydrogen bond donors and acceptors, molecular weight, polar and hydrophobic surface areas, chiral centres, oxygen and nitrogen atoms, and shape index. The remaining molecular descriptors, including clogP, number of rotatable bonds and number of aromatic rings, did not show any significant difference when comparing the two compound sets. Molecular similarity and chemical space analysis identified natural products that were structurally diverse from CRAD. Prediction of the pharmacokinetic properties and drug-likeness of these natural products identified over 50 % with desirable drug-like properties. Nearly 70 % of all natural products were identified as potentially promiscuous compounds. Structure–activity landscape analysis highlighted compound pairs that form ‘activity cliffs’. In all, prioritization strategies for the NAA were proposed.ConclusionsChemo-informatic profiling of NAA and CRAD have produced a wealth of information that may guide decisions and facilitate anti-malarial drug development from natural products. Articulation of the information provided within an interactive data-mining environment led to a prioritized list of NAA.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1087-y) contains supplementary material, which is available to authorized users.

IN SILICOSCREENING AND MOLECULAR DYNAMIC SIMULATION STUDIES OF POTENTIAL SMALL MOLECULE IMMUNOMODULATORS OF THE KIR2DS2 RECEPTOR

“…was used to analyze potency the compounds based on their size and lipophilicity [41]. The LEM used include Lipophilic Efficiency (LE), Ligand-Efficiency dependent Lipophilicity (LEDL), and Ligand Lipophilicity Efficiency (LLE).…”

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