{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T19:17:59Z","timestamp":1789154279547,"version":"build-2803163510"},"reference-count":42,"publisher":"American Chemical Society (ACS)","issue":"20","license":[{"start":{"date-parts":[[2020,5,12]],"date-time":"2020-05-12T00:00:00Z","timestamp":1589241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP17am0101086"],"award-info":[{"award-number":["JP17am0101086"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,5,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Fibrodysplasia ossificans progressiva (FOP) is a rare but severe genetic disorder in which acute inflammation elicits progressive heterotopic ossification in the muscles, tendons, and ligaments. Classic FOP is caused by the R206H mutation in ALK2\/ACVR1. While several activin receptor-like kinase 2 (ALK2) inhibitors were found to be efficacious in animal models of FOP, most of the ALK2 (R206H) inhibitors lacked sufficient oral bioavailability for efficacy. Previously, the synthesis of a series of novel bis-heteroaryl pyrazole-based ALK2 (R206H) inhibitors that achieved both substantial potency and an improved ADMET profile was reported. In the present study, the detailed procedure of the in silico approach employed to identify the initial bis-heteroaryl pyrazole-based ALK2 (R206H) inhibitor RK-59638 and the analysis of the ALK2 (R206H) RK-59638 complex structure to guide the synthetic optimization of the chemical series, obtaining RK-71807 showing improved potency and metabolic stability, were described. According to the initial in silico screening, the screening efficiencies and chemical diversity of the hit compounds of both ligand-based and structure-based methods were evaluated. Then, X-ray structures of ALK2 (R206H) and the inhibitors were analyzed to assess the structure\u2013activity relationships of the synthesized compounds. The 3D-RISM analysis indicated the existence of the additional hydrogen bond via water molecules restricting the attachment point in the pyrazole scaffold. The quantum mechanics calculation of the newly determined ALK2 (R206H) RK-71807 complex structure using a fragment molecular orbital method and pair interaction energy decomposition analysis was employed to evaluate the interaction energies between the inhibitor and each of the amino acid residues and decompose them to electrostatic, exchange-repulsion, and charge transfer energies. The pattern of decomposed interaction energies was then compared to that formed by RK-59638 and LDN-193189 to investigate the structural basis of ALK2 (R206H) inhibition.<\/jats:p>","DOI":"10.1021\/acsomega.9b04245","type":"journal-article","created":{"date-parts":[[2020,5,12]],"date-time":"2020-05-12T11:46:26Z","timestamp":1589283986000},"page":"11411-11423","source":"Crossref","is-referenced-by-count":16,"title":["Structural Basis of Activin Receptor-Like Kinase 2\n(R206H) Inhibition by Bis-heteroaryl Pyrazole-Based Inhibitors for\nthe Treatment of Fibrodysplasia Ossificans Progressiva Identified\nby the Integration of Ligand-Based and Structure-Based Drug Design\nApproaches"],"prefix":"10.1021","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0660-5559","authenticated-orcid":true,"given":"Tomohiro","family":"Sato","sequence":"first","affiliation":[{"name":"RIKEN Center for Biosystems Dynamics Research , , 1\u22127\u221222 Suehiro-cho , Tsurumi-ku, 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Center for Biosystems Dynamics Research , , 1\u22127\u221222 Suehiro-cho , Tsurumi-ku, ,","place":["Yokohama, Japan, 230-0045"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomonori","family":"Taguri","sequence":"additional","affiliation":[{"name":"RIKEN Center for Sustainable Resource Science , , 2\u22121 Hirosawa , , ,","place":["Wako, Saitama, Japan, 351-0198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takehisa","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"RIKEN Center for Biosystems Dynamics Research , , 1\u22127\u221222 Suehiro-cho , Tsurumi-ku, ,","place":["Yokohama, Japan, 230-0045"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshifumi","family":"Fujii","sequence":"additional","affiliation":[{"name":"RIKEN Systems and Structural Biology Center , , 1\u22127\u221222 Suehiro-cho , Tsurumi-ku, ,","place":["Yokohama, Japan, 230-0045"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Handa","sequence":"additional","affiliation":[{"name":"RIKEN Systems and Structural Biology Center , , 1\u22127\u221222 Suehiro-cho , Tsurumi-ku, ,","place":["Yokohama, Japan, 230-0045"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Tanaka","sequence":"additional","affiliation":[{"name":"RIKEN Center for Biosystems Dynamics Research , , 1\u22127\u221222 Suehiro-cho , Tsurumi-ku, ,","place":["Yokohama, Japan, 230-0045"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikako","family":"Shirouzu","sequence":"additional","affiliation":[{"name":"RIKEN Center for Biosystems Dynamics Research , , 1\u22127\u221222 Suehiro-cho , Tsurumi-ku, ,","place":["Yokohama, Japan, 230-0045"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3133-7338","authenticated-orcid":true,"given":"Shigeyuki","family":"Yokoyama","sequence":"additional","affiliation":[{"name":"RIKEN Systems and Structural Biology Center , , 1\u22127\u221222 Suehiro-cho , Tsurumi-ku, ,","place":["Yokohama, Japan, 230-0045"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinobu","family":"Hashizume","sequence":"additional","affiliation":[{"name":"RIKEN Program for Drug Discovery and Medical Technology Platforms , 2\u22121 Hirosawa , , ,","place":["Wako, Saitama, Japan, 351-0198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Miyazono","sequence":"additional","affiliation":[{"name":"The University of Tokyo , , 7\u22123\u22121 Hongo , Bunkyo-ku, ,","place":["Tokyo, Japan, 113-0033"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroo","family":"Koyama","sequence":"additional","affiliation":[{"name":"RIKEN Center for Sustainable Resource Science , , 2\u22121 Hirosawa , , ,","place":["Wako, Saitama, Japan, 351-0198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3761-9504","authenticated-orcid":true,"given":"Teruki","family":"Honma","sequence":"additional","affiliation":[{"name":"RIKEN Center for Biosystems Dynamics Research , , 1\u22127\u221222 Suehiro-cho , Tsurumi-ku, ,","place":["Yokohama, Japan, 230-0045"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,5,12]]},"reference":[{"key":"2026090210494738500_cit1","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/ng1783","article-title":"A Recurrent\nMutation in the BMP Type I Receptor ACVR1 Causes Inherited and Sporadic\nFibrodysplasia Ossificans 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