<i>In silico</i> screening of selective ATP mimicking inhibitors targeting the <i>Plasmodium falciparum</i> Grp94

Abstract

<i>Plasmodium falciparum</i> parasites export more than 400 proteins to remodel the host cell environment and increase its chances of surviving and reproducing. The endoplasmic reticulum (ER) plays a central role in protein export by facilitating protein sorting and folding. The ER resident member of the Hsp90 family, glucose-regulated protein 94 (Grp94), is a molecular chaperone that facilitates the proper folding of client proteins in the ER lumen. In <i>P. falciparum,</i> Grp94 (<i>Pf</i>Grp94) is essential for parasite survival, rendering it a promising anti-malarial drug target. Despite this, its druggability has not been fully explored. Consequently, this study sought to identify small molecule inhibitors targeting the <i>Pf</i>Grp94. Potential small molecule inhibitors of <i>Pf</i>Grp94 were designed and screened using in silico studies. Molecular docking studies indicate that two novel compounds, Compound S and Compound Z selectively bind to <i>Pf</i>Grp94 over its human homologues. Comparatively, Compound Z had a higher affinity for <i>Pf</i>Grp94 than Compound S. Further interrogation of the inhibitor binding using molecular dynamics (MD) analysis confirmed that Compound Z formed stable binding poses within the ATP-binding pocket of the PfGrp94 N-terminal domain (NTD) during the 250 ns simulation run. <i>Pf</i>Grp94 interacted with Compound Z through hydrogen bonding and hydrophobic interactions with residues Asp 148, Asn 106, Gly 152, Ile 151 and Lys 113. Based on the findings of this study, Compound Z could serve as a competitive and selective inhibitor of <i>Pf</i>Grp94 and may be useful as a starting point for the development of a potential drug for malaria.