https://orcid.org/0000-0003-3732-5063
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Abstract
Compared to the previous year, there has been an increase of nearly 2 million malaria cases in 2021. The emergence of drug-resistant strains of Plasmodium falciparum, the most deadly malaria parasite, has led to a decline in the effectiveness of existing antimalarial drugs. To address this problem, the present study aimed to identify natural compounds with the potential to inhibit multiple validated antimalarial drug targets. The natural compounds from the Natural Product Activity and Species Source (NPASS) database were screened against ten validated drug targets of Plasmodium falciparum using a structure-based molecular docking method. Twenty compounds, with targets ranging from three to five, were determined as the top hits. The molecular dynamics simulations of the top six complexes (NPC246162 in complex with PfAdSS, PfGDH, and PfNMT; NPC271270 in complex with PfCK, PfGDH, and PfdUTPase) confirmed their stable binding affinity in the dynamic environment. The Tanimoto coefficient and distance matrix score analysis show the structural divergence of all the hit compounds from known antimalarials, indicating minimum chances of cross-resistance. Thus, we propose further investigating these compounds in biochemical and parasite inhibition studies to reveal the real therapeutic potential. If found successful, these compounds may be a new avenue for future drug discovery efforts to combat existing antimalarial drug resistance.
Communicated by Ramaswamy H. Sarma
Acknowledgments
BN is thankful to the Department of Biotechnology (DBT), India, for providing a research fellowship. DP is thankful to the Central University of Rajasthan for providing a research facility.
Authors’ contributions
Biswajit Naik, Nidhi Gupta, and Dhaneswar Prusty wrote the main manuscript. Biswajit Naik, Nidhi Gupta, Priya Godara, Varshita Srivastava, and Prateek Kumar performed the methodology and prepared the figures. Formal analysis and investigation by Biswajit Naik, Nidhi Gupta, Rajanish Giri, Vijay Kumar Prajapati, Kailash C. Pandey, and Dhaneswar Prusty. All the authors reviewed the manuscript.
Disclosure statement
No potential conflict of interest was reported by the author(s).