An in silico structural and functional analysis of P falciparum epigenetic regulators PfMYST and PfRUVBL to explore their potential as antimalarial drug targets

Abstract

Malaria continues to be a global health challenge, especially in sub-Saharan Africa and other endemic areas, where it continues to take the lives of millions of people, particularly children under the age of five and pregnant women. The alarming emergence of resistance in malaria parasite against artemisinin-based combination therapy (first line drug therapy), which has long been the cornerstone of malaria treatment, emphasizes the urgent need to identify molecular targets and develop new antimalarial drugs. In this study, a computer-aided drug discovery approach was employed to explore the potential of two essential epigenetic regulators of the P. falciparum parasite: PfRUVBL and PfMYST as molecular targets for antimalarial therapy. In silico structural characterization of target proteins was performed and results revealed significant distinctions between Plasmodium and human homologs suggesting these epigenetic regulators as potential antimalarial drug targets. Further, structure-based vHTS followed by MD Simulation was performed to screen a library of small molecules which led to the identification of two Plasmodium specific compounds for both PfRUVBL1 and PfMYST proteins. newline newlineIn the second part, we examined the phylogenetic and evolutionary aspects of the RUVBL protein family and two MYST family members (KAT5 and KAT8) across all domains of life to understand how these proteins have evolved in different life forms. Using HMM-profile based methods, homologs of the RUVBL protein family were identified in all domains of life from bacteria to humans. Phylogenetic analysis demonstrated the divergence of the RUVBL family into three distinct clades, with multiple paralogs identified in the species of eukaryotes, providing invaluable insights into the evolution of these proteins. Furthermore, our exploration of KAT5 and KAT8 homologs illuminated their presence in eukaryotes exclusively, with notable divergence within the Animal kingdom. Evolutionary analyses unveiled diversifying selection acting on these genes, partic