In silico screening of selective ATP mimicking inhibitors targeting the Plasmodium falciparum Grp94

Abstract

Plasmodium falciparum 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 P. falciparum, Grp94 (PfGrp94) 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 PfGrp94. Potential small molecule inhibitors of PfGrp94 were designed and screened using in silico studies. Molecular docking studies indicate that two novel compounds, Compound S and Compound Z selectively bind to PfGrp94 over its human homologues. Comparatively, Compound Z had a higher affinity for PfGrp94 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. PfGrp94 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 PfGrp94 and may be useful as a starting point for the development of a potential drug for malaria.

Communicated by Ramaswamy H. Sarma

Keywords:

• Malaria
• Plasmodium falciparum
• Grp94
• molecular docking and dynamics
• small molecule inhibitors

Acknowledgements

We thank the South African Council for Scientific and Industrial Research (CSIR) centre for high performance computing (CHPC) for Schrodinger suite and the BioSolveIT Software company in Sankt Augustin, Germany for SeeSAR software access.

Authors contributions

MLS: conducted some of the experiments, interpreted the data. FLM: conducted some of the experiments, interpreted the data, wrote the manuscript, IK: analysed and interpreted the data. ES: analysed and interpreted the data. TZ: conceptualised the study, interpreted data, wrote the manuscript, supervised, and implemented the study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data presented in the current study are contained within the manuscript/Supplementary Materials and accessible from the corresponding author including simulation videos upon request.

Additional information

Funding

The study was supported in part by the Department of Science and Technology/National Research Foundation (NRF) of South Africa (Grant numbers, 129401 & 145405) awarded to T.Z; and (Grant number 131724) awarded to MLS. The authors would like to acknowledge the Stellenbosch University Sub-Committee B for financial support to TZ. South Africa National Research Foundation; National Research Foundation South Africa; South African National Research Foundation.