{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:33:10Z","timestamp":1791919990064,"version":"4.3.4"},"reference-count":38,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T00:00:00Z","timestamp":1668556800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The past decade has seen most antimalarial drugs lose their clinical potency stemming from parasite resistance. Despite immense efforts by researchers to mitigate this global scourge, a breakthrough is yet to be achieved, as most current malaria chemotherapies suffer the same fate. Though the etiology of parasite resistance is not well understood, the parasite\u2019s complex life has been implicated. A drug-combination therapy with artemisinin as the central drug, artemisinin-based combination therapy (ACT), is currently the preferred malaria chemotherapy in most endemic zones. The emerging concern of parasite resistance to artemisinin, however, has compromised this treatment paradigm. Membrane-bound Ca2+-transporting ATPase and endocytosis pathway protein, Kelch13, among others, are identified as drivers in plasmodium parasite resistance to artemisinin. To mitigate parasite resistance to current chemotherapy, computer-aided drug design (CADD) techniques have been employed in the discovery of novel drug targets and the development of small molecule inhibitors to provide an intriguing alternative for malaria treatment. The evolution of plasmepsins, a class of aspartyl acid proteases, has gained tremendous attention in drug discovery, especially the non-food vacuole. They are expressed at multi-stage of the parasite\u2019s life cycle and involve in hepatocytes\u2019 egress, invasion, and dissemination of the parasite within the human host, further highlighting their essentiality. In silico exploration of non-food vacuole plasmepsin, PMIX and PMX unearthed the dual enzymatic inhibitory mechanism of the WM382 and 49c, novel plasmepsin inhibitors presently spearheading the search for potent antimalarial. These inhibitors impose structural compactness on the protease, distorting the characteristic twist motion. Pharmacophore modeling and structure activity of these compounds led to the generation of hits with better affinity and inhibitory prowess towards PMIX and PMX. Despite these headways, the major obstacle in targeting PM is the structural homogeneity among its members and to human Cathepsin D. The incorporation of CADD techniques described in the study at early stages of drug discovery could help in selective inhibition to augment malaria chemotherapy.<\/jats:p>","DOI":"10.3390\/molecules27227915","type":"journal-article","created":{"date-parts":[[2022,11,17]],"date-time":"2022-11-17T06:19:01Z","timestamp":1668665941000},"page":"7915","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Bridging the Gap in Malaria Parasite Resistance, Current Interventions, and the Way Forward from in Silico Perspective: A Review"],"prefix":"10.3390","volume":"27","author":[{"given":"Ransford Oduro","family":"Kumi","sequence":"first","affiliation":[{"name":"Molecular Bio-Computation and Drug Design Laboratory, School of Health Sciences, Westville Campus, University of KwaZulu-Natal, Durban 4001, South Africa"},{"name":"Department of Industrial and Health Sciences, Faculty of Applied Sciences, Takoradi Technical University, Takoradi 256, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belinda","family":"Oti","sequence":"additional","affiliation":[{"name":"Department of Industrial and Health Sciences, Faculty of Applied Sciences, Takoradi Technical University, Takoradi 256, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nader E.","family":"Abo-Dya","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia"},{"name":"Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed Issa","family":"Alahmdi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud E. S.","family":"Soliman","sequence":"additional","affiliation":[{"name":"Molecular Bio-Computation and Drug Design Laboratory, School of Health Sciences, Westville Campus, University of KwaZulu-Natal, Durban 4001, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"181","DOI":"10.4172\/jpb.1000405","article-title":"Structural Investigation and In-silico Characterization of Plasmepsins from Plasmodium falciparum","volume":"9","author":"Nair","year":"2016","journal-title":"J. Proteom. Bioinform."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Talapko, J., \u0160krlec, I., Alebi\u0107, T., Juki\u0107, M., and V\u010dev, A. (2019). Malaria: The Past and the Present. 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