{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T14:53:11Z","timestamp":1770907991527,"version":"3.50.1"},"reference-count":105,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Incentive Funding for Rated Researchers Programme of the NRF, South Africa","award":["RA22111973834"],"award-info":[{"award-number":["RA22111973834"]}]},{"name":"Government of India, FIST Grant","award":["SR\/FST\/PG College\/2009"],"award-info":[{"award-number":["SR\/FST\/PG College\/2009"]}]},{"name":"Goverment of India, DBT Star College Scheme","award":["HRD-11011\/28\/2021-HRD-DBT"],"award-info":[{"award-number":["HRD-11011\/28\/2021-HRD-DBT"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The increasing threat of zoonotic malaria parasites of humans, such as Plasmodium knowlesi, make the search for improved pharmacotherapy imperative. Using protein sequence and structural analyses, phylogenetics, protein network mapping, protein\u2013ligand interaction, and small molecule docking studies, we have identified for the first time the predicted structure, function, and druggability of the P. knowlesi heat shock protein 90s (PkHsp90s). Four isoforms were identified (in the cytosol, endoplasmic reticulum, mitochondrion, and apicoplast), and key structural differences were elucidated compared to human Hsp90s. In particular, the glycine-rich helix loop (GHL) motif of cytosolic PkHsp90 was predicted to have a straight conformation that forms a plasmodial-specific hydrophobic extension of the lid domain of the ATP-binding site, which was not observed for the cytosolic human Hsp90s, HSPC1 (Hsp90\u03b1), and HSPC3 (Hsp90\u03b2). Virtual screening identified for the first time a number of compounds from the ZINC database (ZINC22007970, ZINC724661072, and ZINC724661078) that were predicted to bind strongly to the GHL-associated pocket of PkHsp90, with weak or no binding to HSPC1. This study has provided a molecular framework in support of rational drug design, targeting PkHsp90s as a promising route for antimalarial drug development in the fight against zoonotic malaria.<\/jats:p>","DOI":"10.3390\/ijms262412065","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T13:32:37Z","timestamp":1765805557000},"page":"12065","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Plasmodium knowlesi Heat Shock Protein 90s: In Silico Analysis Reveals Unique Druggable Structural Features"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3669-3542","authenticated-orcid":false,"given":"Michael O.","family":"Daniyan","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife 220005, Nigeria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7202-3912","authenticated-orcid":false,"given":"Harpreet","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Hans Raj Mahila Maha Vidyalaya, Jalandhar 144008, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0778-8577","authenticated-orcid":false,"given":"Gregory L.","family":"Blatch","sequence":"additional","affiliation":[{"name":"The Vice Chancellery, The University of Notre Dame Australia, Fremantle, WA 6959, Australia"},{"name":"Biomedical Biotechnology Research Unit, Department of Biochemistry, Microbiology and Bioinformatics, Rhodes University, Makhanda 6140, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2025). 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