{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T11:14:49Z","timestamp":1788174889437,"version":"build-2803163510"},"reference-count":55,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/100031746","name":"Science for Africa Foundation","doi-asserted-by":"publisher","award":["DEL-22-014"],"award-info":[{"award-number":["DEL-22-014"]}],"id":[{"id":"10.13039\/100031746","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Bioinform Biol Insights"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:p>\n                    <jats:italic toggle=\"yes\">Plasmodium falciparum<\/jats:italic>\n                    Calcium-Dependent Protein Kinase 4 (\n                    <jats:italic toggle=\"yes\">Pf<\/jats:italic>\n                    CDPK4) is a validated target for malaria transmission-blocking interventions, as its inhibition disrupts male gametocyte exflagellation. Hexahydroquinolines (HHQs) have emerged as promising gametocytocidal agents. This study aimed to design novel HHQs as potential\n                    <jats:italic toggle=\"yes\">Pf<\/jats:italic>\n                    CDPK4 inhibitors with good binding affinity, favourable pharmacokinetics, and structural stability. A library of 20,000 novel HHQ analogs was generated using genetic algorithm-driven\n                    <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                    molecular design in AlvaBuilder and systematically filtered through a pipeline comprising machine-learning-based bioactivity prediction, PAINS removal, pharmacophore modeling, ADMET screening, and structure-based virtual screening. Top-ranking compounds underwent bioisosteric optimization and were evaluated using 300 ns molecular dynamics simulations and density functional theory (DFT) calculations. Comparative\n                    <jats:italic toggle=\"yes\">in silico<\/jats:italic>\n                    validation against known inhibitor Bumped Kinase Inhibitor-1 (BKI-1) and the co-crystallized ligand DXR as controls demonstrated that four HHQ analogs exhibited comparable binding affinities and stable interactions with key residues within the ATP-binding pocket. Favourable ADMET profiles, dynamic stability, and supportive electronic properties further reinforced their inhibition potential. These findings provide biologically meaningful computational evidence supporting HHQ scaffolds as potential\n                    <jats:italic toggle=\"yes\">Pf<\/jats:italic>\n                    CDPK4 inhibitors and demonstrate the utility of integrated bioinformatics approaches for malaria transmission-blocking drug discovery. Further experimental validation is required to confirm the inhibitory activities of the identified hexahydroquinoline compounds.\n                  <\/jats:p>","DOI":"10.1177\/11779322261483607","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T19:38:06Z","timestamp":1787945886000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["De Novo Molecular Design and Bioactivity Prediction of Novel Hexahydroquinolines as\n                    <i>Plasmodium falciparum<\/i>\n                    Calcium-Dependent Protein Kinase 4 (CDPK4) Inhibitors"],"prefix":"10.1177","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0136-1732","authenticated-orcid":false,"given":"Gbolahan O.","family":"Oduselu","sequence":"first","affiliation":[{"name":"University of Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damilola S.","family":"Bodun","sequence":"additional","affiliation":[{"name":"Covenant University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olayinka O.","family":"Ajani","sequence":"additional","affiliation":[{"name":"Covenant University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Conway","sequence":"additional","affiliation":[{"name":"London School of Hygiene and Tropical Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas N.","family":"Amenga-Etego","sequence":"additional","affiliation":[{"name":"University of Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wellington","family":"Oyibo","sequence":"additional","affiliation":[{"name":"University of Lagos"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon A.","family":"Awandare","sequence":"additional","affiliation":[{"name":"University of Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"e_1_3_5_2_2","volume-title":"World Malaria Report 2024","author":"World Health Orgnization (WHO)","year":"2024","unstructured":"World Health Orgnization (WHO). 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