Integrative in vitro and in silico approaches for understanding host pathogen interactions in human malaria parasite for drug discovery

Abstract

Malaria is an infectious parasitic disease that continues to be a significant global health issue affecting several people around the world. Artemisinin Combination Therapy (ACT) is well-established chemotherapy for malaria treatment. Emerging resistance to existing ACT in South-East Asia creates a challenge in the control and elimination of malaria. Thus, the development of new antimalarial chemotherapy to control and eliminate malaria is sorely needed. In the current study, discovering a new class of antimalarial drugs has been done to combine medicinal chemistry with an understanding of parasite biology. The thesis encompasses the study of the effectiveness of three different compounds, Prasugrel, Alisporivir, and Dependensin derivatives. In our study, we indicated the presence of purinergic signalling in growth and development of malaria parasite and advocated the repurposing of P2Y type purinergic receptor inhibitor Prasugrel, a FDA approved drug as valid option for antimalarial treatment. Furthermore, we suggested druggability of GPCR like receptor PfSR12 through Prasugrel. Furthermore, in another study, we report the successful repurposing of the anti-Hepatitis C Virus drug Alisporivir against multiple drug-resistant strains of P. falciparum with a potentially new mechanism of action. In summary, this work provides mechanistic insights which lead to a better understanding of the interaction between host and pathogen for novel drug target identification. It also lends weight to developing new pharmacological approaches that can pave the way for better therapeutic interventions against drug-resistant parasites. Lastly, we have utilized phenotype-based screening to investigate the naturally inspired novel class of synthetic compounds derivatives of Dependensin to evaluate antimalarial potential against P. falciparum. Here, we present the evaluation of novel naturally inspired plant-based compounds (Dependensin derivatives) against the malaria parasite erythrocytic stage using various in silico and in vitro approaches. We have used quantitative structure-activity (QSAR) analysis to generate an efficient model for the prediction of compounds activity. Together, all these screening and evaluation of different compounds using various approaches can be used for anti-malarial drug development.