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We performed a virtual screening using the ZINC library comprising approximately 90,000 natural compounds. We applied Lipinski\u2019s rule of five, absorption, distribution, metabolism, excretion, and toxicity properties, and pan-assay interference compounds filter to eliminate promiscuous binders. Subsequently, the filtered compounds underwent molecular docking to predict their binding affinity and interactions with the CDK8 protein. Interaction analysis were carried out to elucidate the interaction mechanism of the screened hits with binding pockets of the CDK8. The ZINC02152165, ZINC04236005, and ZINC02134595 were selected with appreciable specificity and affinity with CDK8. An all-atom molecular dynamic (MD) simulation followed by essential dynamics was performed for 200 ns. Taken together, the results suggest that ZINC02152165, ZINC04236005, and ZINC02134595 can be harnessed as potential leads in therapeutic development. Moreover, the binding of the molecules brings change in protein conformation in a way that blocks the ATP-binding site of the protein, obstructing its kinase activity. These new findings from natural products offer insights into the molecular mechanisms underlying CDK8 inhibition. CDK8 was previously associated with behavioral and neurological diseases such as autism spectrum disorder, and cancers, for example, colorectal, prostate, breast, and acute myeloid leukemia. Hence, we call for further research and experimental validation, and with an eye to inform future clinical drug discovery and development in these therapeutic fields.<\/jats:p>","DOI":"10.1089\/omi.2024.0128","type":"journal-article","created":{"date-parts":[[2024,8,16]],"date-time":"2024-08-16T05:00:27Z","timestamp":1723784427000},"page":"478-488","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":4,"title":["Enriching Anticancer Drug Pipeline with Potential Inhibitors of Cyclin-Dependent Kinase-8 Identified from Natural Products"],"prefix":"10.1177","volume":"28","author":[{"family":"Zehra","sequence":"first","affiliation":[{"name":"Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Afzal","family":"Hussain","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed F.","family":"AlAjmi","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Romana","family":"Ishrat","sequence":"additional","affiliation":[{"name":"Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3663-4940","authenticated-orcid":false,"given":"Md Imtaiyaz","family":"Hassan","sequence":"additional","affiliation":[{"name":"Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2024,9,3]]},"reference":[{"key":"e_1_3_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2021.188568"},{"key":"e_1_3_6_3_1","doi-asserted-by":"publisher","DOI":"10.1039\/C4FD00167B"},{"key":"e_1_3_6_4_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389203715666140327114232"},{"key":"e_1_3_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molliq.2012.07.003"},{"key":"e_1_3_6_6_1","doi-asserted-by":"publisher","DOI":"10.2174\/138620711797537102"},{"key":"e_1_3_6_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.2007"},{"key":"e_1_3_6_8_1","doi-asserted-by":"publisher","DOI":"10.24198\/ijcb.v2i1.46322"},{"key":"e_1_3_6_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20112783"},{"key":"e_1_3_6_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.6b00044"},{"key":"e_1_3_6_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10858-007-9208-0"},{"key":"e_1_3_6_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.24890"},{"key":"e_1_3_6_13_1","article-title":"Discovery studio","author":"Biovia DS","year":"2016","unstructured":"Biovia DS. 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