Antimalarial drug development from phytomedicine: Chemoinformatic and pharmacological studies

Abstract

Background: Identification of new compounds, preferably with novel mechanism of actions (MOA), is highly desirable to circumvent resistance of Plasmodium falciparum to current antimalarial drugs. Although large numbers of phytochemicals have shown good in-vitro antiplasmodial activities but hardly any have made it through the antimalarial drug development pipeline. Chemoinformatic and pharmacological characterization of these phytochemicals may be able to identify those with possible unique MOA and desirable pharmacological profile, which is essential for in-vivo/clinical evaluation, hence aid antimalarial drug development. Our research questions included: How similar/diverse are these phytochemicals from current antimalarial drugs? Do these phytochemicals have desirable DMPK (Drug Metabolism and Pharmacokinetics) profiles? What are their binding affinities and mode to drug targets in P.falciparum? Methods & Materials: Chemoinformatic characterization done include: molecular structure and pharmacophore similarities (Tanimoto coefficient) between these phytochemicals and current antimalarial drugs as well as scaffold analysis to identify unique substructures. Similarity matrices were constructed and data visualized as cluster trees and heat maps. For pharmacological characterization, Molecular Operating Environment, Discovery studio and SMARTcyp software were used to compute molecular features that define DMPK profile and to simulate the binding of these phytochemicals to drug targets in P.falciparum. Results: The results show that the majority of these phytochemicals (93%) have substructural features that are diverse from current antimalarial drugs but similar pharmacophore features. Unique chemical scaffolds were identified and up to 64% possess desirable DMPK profiles. Molecular docking simulations showed that these phytochemicals interact with important amino acid residues within drug targets in P.falciparum. Conclusion: The pharmacophore features, unique scaffolds and the highly diversified chemical space of these phytochemicals from current antimalarial drugs gives them the potential to interact with novel drug targets in P.falciparum hence may possess a unique MOA. A good number of these phytochemicals showed good DMPK profiles that may be favourable for them to be moved into clinical evaluation. Molecular docking of these phytochemicals showed important interaction with viable drug targets in P.falciparum and suggest possible MOA. Overall, the data generated for each phytochemicals may allow rational selection of phytochemicals that may be successfully moved through the antimalarial drug development pipeline.