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While conformational changes are increasingly discussed, the impact of drug compound flexibility remains underexplored because of experimental limitations. In this study, we employ two-dimensional replica-exchange MD simulations to investigate how c-Src kinase binds to PP1, a small inhibitor, and to dasatinib, a larger, more flexible inhibitor. Simulations totaling 600 \u03bcs revealed frequent binding and unbinding events, yielding statistically converged information about the binding pathways. While both inhibitors follow multiple binding pathways, a notable difference emerges in their binding mechanisms on the free-energy profiles: PP1 is rigid along the binding path, whereas dasatinib substantially changes its conformation at different stages in the pathway to the canonical pose. Conformational analysis reveals distinct conformers of dasatinib, including a hidden intermediate, which helps to avoid trapping at the salt-bridge pair linking the \u03b23 strand and the \u03b1C-helix of the c-Src kinase. These results, distinct from previous computational studies, demonstrate that inhibitor size and flexibility affect binding mechanisms and have implications on kinetics.<\/jats:p>","DOI":"10.1021\/acs.jpclett.6c02620","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T01:02:03Z","timestamp":1789520523000},"page":"11119-11128","source":"Crossref","is-referenced-by-count":0,"title":["Impact of Inhibitor Size and Flexibility on the Binding\nPathways to c-Src Kinase"],"prefix":"10.1021","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2865-6461","authenticated-orcid":true,"given":"Ai","family":"Shinobu","sequence":"first","affiliation":[{"name":"RIKEN Center for Biosystems Dynamics Research , 7-1-26 minatojima-minamimachi, Chuo-ku , , ,","place":["Kobe, Hyogo, Japan, 650-0047"]},{"name":"The University of Osaka , , 2-8 Yamadaoka, Suita , , ,","place":["Osaka, Japan, 565-0871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3752-6554","authenticated-orcid":true,"given":"Suyong","family":"Re","sequence":"additional","affiliation":[{"name":"RIKEN Center for Biosystems Dynamics Research , 7-1-26 minatojima-minamimachi, Chuo-ku , , ,","place":["Kobe, Hyogo, Japan, 650-0047"]},{"name":"National Institutes of Biomedical Innovation, Health, and Nutrition , , 3-17 Senrioka Shinmachi, Settu-shi , ,","place":["Osaka, Japan, 566-0002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5626-1291","authenticated-orcid":true,"given":"Hiraku","family":"Oshima","sequence":"additional","affiliation":[{"name":"RIKEN Center for Biosystems Dynamics Research , 7-1-26 minatojima-minamimachi, Chuo-ku , , ,","place":["Kobe, Hyogo, Japan, 650-0047"]},{"name":"University of Hyogo , , 3-2-1 Kouto, Kamigori-cho , , ,","place":["Ako-gun, Hyogo, Japan, 678-1297"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9738-9216","authenticated-orcid":true,"given":"Yuji","family":"Sugita","sequence":"additional","affiliation":[{"name":"RIKEN Center for Biosystems Dynamics Research , 7-1-26 minatojima-minamimachi, Chuo-ku , , ,","place":["Kobe, Hyogo, Japan, 650-0047"]},{"name":"RIKEN Pioneering Research Institute , , 2-1 Hirosawa, Wako , ,","place":["Saitama, Japan, 351-0198"]},{"name":"RIKEN Center for Computational Science , 7-1-26 minatojima-minamimachi, Chuo-ku , , ,","place":["Kobe, Hyogo, Japan, 650-0047"]},{"name":"University of Tokyo , , 7-3-1 Hongo, Bunkyo-ku , ,","place":["Tokyo, Japan, 113-0033"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"issue":"2","key":"2026100109090596400_cit1","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1021\/acs.jmedchem.1c00963","article-title":"Small Molecule\nKinase Inhibitor Drugs\n(1995\u20132021): Medical Indication, Pharmacology, and Synthesis","volume":"65","author":"Ayala-Aguilera","year":"2022","journal-title":"J. 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