Application of multi-target phytotherapeutic concept in malaria drug discovery: a systems biology approach in biomarker identification

Abstract

There is an urgent need for new anti-malaria drugs with broad therapeutic potential and novel mode of action, for effective treatment and to overcome emerging drug resistance. Plant-derived anti-malarials remain a significant source of bioactive molecules in this regard. The multicomponent formulation forms the basis of phytotherapy. Mechanistic reasons for the poly-pharmacological effects of plants constitute increased bioavailability, interference with cellular transport processes, activation of pro-drugs/deactivation of active compounds to inactive metabolites and action of synergistic partners at different points of the same signaling cascade. These effects are known as the multi-target concept. However, due to the intrinsic complexity of natural products-based drug discovery, there is need to rethink the approaches toward understanding their therapeutic effect. This review discusses the multi-target phytotherapeutic concept and its application in biomarker identification using the modified reverse pharmacology - systems biology approach. Considerations include the generation of a product library, high throughput screening (HTS) techniques for efficacy and interaction assessment, High Performance Liquid Chromatography (HPLC)-based anti-malarial profiling and animal pharmacology. This approach is an integrated interdisciplinary implementation of tailored technology platforms coupled to miniaturized biological assays, to track and characterize the multi-target bioactive components of botanicals as well as identify potential biomarkers. While preserving biodiversity, this will serve as a primary step towards the development of standardized phytomedicines, as well as facilitate lead discovery for chemical prioritization and downstream clinical development.

Keywords: HPLC-based anti-malarial profiling; High throughput screening (HTS); In vivo pharmacology; Malaria; Multi-target effects; Pharmacokinetics; Phytotherapy; Reverse pharmacology.

Fig. 1

Work flow for the application of metabolomics in analysis of HMs. a HPLC-based activity profiling. b Phytochemical profiling (untargeted metabolomics) Metabolomics-based phytochemical profiling and in vitro bioassays of bioactivities may establish the correlation between specific phytochemicals and different bioactivities leading to the identification of biomarkers

Fig. 2

Isobolograms of the in vitro interactions between differential solvent extracts of a polyherbal product at variable potency ratios (a)-Additive interaction: Chloroquine/chloroquine combination (b)-Antagonistic interaction: Chloroquine/Artemisinin combination (c)-Synergistic interaction: MiB/Pg aqueous extracts combination (d)-Synergistic and antagonistic interactions: MiB/Cs aqueous extracts at different potency combinations [79]