{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:37:42Z","timestamp":1792132662392,"version":"4.4.0"},"reference-count":60,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T00:00:00Z","timestamp":1666569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"Korean government MSIT","doi-asserted-by":"publisher","award":["2022R1A2C1007452"],"award-info":[{"award-number":["2022R1A2C1007452"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Korean government MSIT","doi-asserted-by":"publisher","award":["IBS-R010-A2"],"award-info":[{"award-number":["IBS-R010-A2"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010446","name":"Institute for Basic Science","doi-asserted-by":"publisher","award":["2022R1A2C1007452"],"award-info":[{"award-number":["2022R1A2C1007452"]}],"id":[{"id":"10.13039\/501100010446","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010446","name":"Institute for Basic Science","doi-asserted-by":"publisher","award":["IBS-R010-A2"],"award-info":[{"award-number":["IBS-R010-A2"]}],"id":[{"id":"10.13039\/501100010446","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Missense mutations of leucine-rich repeat kinase 2 (LRRK2), including the G2019S mutant, are responsible for the pathogenesis of Parkinson\u2019s disease. In this work, structure-based virtual screening of a large chemical library was carried out to identify a number of novel inhibitors of the G2019S mutant of LRRK2, the biochemical potencies of which ranged from the low micromolar to the submicromolar level. The discovery of these potent inhibitors was made possible due to the modification of the original protein\u2013ligand binding energy function in order to include an accurate ligand dehydration energy term. The results of extensive molecular docking simulations indicated that the newly identified inhibitors were bound to the ATP-binding site of the G2019S mutant of LRRK2 through the multiple hydrogen bonds with backbone amide groups in the hinge region as well as the hydrophobic interactions with the nonpolar residues in the P-loop, hinge region, and interdomain region. Among 18 inhibitors derived from virtual screening, 4-(2-amino-5-phenylpyrimidin-4-yl)benzene-1,3-diol (Inhibitor 2) is most likely to serve as a new molecular scaffold to optimize the biochemical potency, because it revealed submicromolar inhibitory activity in spite of its low molecular weight (279.3 amu). Indeed, a highly potent inhibitor (Inhibitor 2n) of the G2019S mutant was derived via the structure-based de novo design using the structure of Inhibitor 2 as the molecular core. The biochemical potency of Inhibitor 2n surged to the nanomolar level due to the strengthening of hydrophobic interactions in the ATP-binding site, which were presumably caused by the substitutions of small nonpolar moieties. Due to the high biochemical potency against the G2019S mutant of LRRK2 and the putatively good physicochemical properties, Inhibitor 2n is anticipated to serve as a new lead compound for the discovery of antiparkinsonian medicines.<\/jats:p>","DOI":"10.3390\/ijms232112825","type":"journal-article","created":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T11:53:55Z","timestamp":1666612435000},"page":"12825","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Structure-Based Virtual Screening and De Novo Design to Identify Submicromolar Inhibitors of G2019S Mutant of Leucine-Rich Repeat Kinase 2"],"prefix":"10.3390","volume":"23","author":[{"given":"Hwangseo","family":"Park","sequence":"first","affiliation":[{"name":"Department of Bioscience and Biotechnology, Sejong University, 209 Neungdong-ro, Kwangjin-gu, Seoul 05006, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taeho","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Bioscience and Biotechnology, Sejong University, 209 Neungdong-ro, Kwangjin-gu, Seoul 05006, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kewon","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea"},{"name":"Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahyoung","family":"Jang","sequence":"additional","affiliation":[{"name":"Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea"},{"name":"Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9371-1730","authenticated-orcid":false,"given":"Sungwoo","family":"Hong","sequence":"additional","affiliation":[{"name":"Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea"},{"name":"Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.neuron.2004.10.023","article-title":"Cloning of the gene containing mutations that cause PARK8-linked Parkinson\u2019s disease","volume":"44","author":"Jain","year":"2004","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"eaar5429","DOI":"10.1126\/scitranslmed.aar5429","article-title":"LRRK2 activation in idiopathic Parkinson\u2019s disease","volume":"10","author":"Hoffman","year":"2018","journal-title":"Sci. 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