{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T14:36:48Z","timestamp":1762353408306,"version":"build-2065373602"},"reference-count":61,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T00:00:00Z","timestamp":1696204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation (NRF) of Korea","award":["2021R1F1A10641141261782064340102"],"award-info":[{"award-number":["2021R1F1A10641141261782064340102"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Thromboembolic disorders, arising from abnormal coagulation, pose a significant risk to human life in the modern world. The FDA has recently approved several anticoagulant drugs targeting factor Xa (FXa) to manage these disorders. However, these drugs have potential side effects, leading to bleeding complications in patients. To mitigate these risks, coagulation factor IXa (FIXa) has emerged as a promising target due to its selective regulation of the intrinsic pathway. Due to the high structural and functional similarities of these coagulation factors and their inhibitor binding modes, designing a selective inhibitor specifically targeting FIXa remains a challenging task. The dynamic behavior of protein\u2013ligand interactions and their impact on selectivity were analyzed using molecular dynamics simulation, considering the availability of potent and selective compounds for both coagulation factors and the co-crystal structures of protein\u2013ligand complexes. Throughout the simulations, we examined ligand movements in the binding site, as well as the contact frequencies and interaction fingerprints, to gain insights into selectivity. Interaction fingerprint (IFP) analysis clearly highlights the crucial role of strong H-bond formation between the ligand and D189 and A190 in the S1 subsite for FIXa selectivity, consistent with our previous study. This dynamic analysis also reveals additional FIXa-specific interactions. Additionally, the absence of polar interactions contributes to the selectivity for FXa, as observed from the dynamic profile of interactions. A contact frequency analysis of the protein\u2013ligand complexes provides further confirmation of the selectivity criteria for FIXa and FXa, as well as criteria for binding and activity. Moreover, a ligand movement analysis reveals key interaction dynamics that highlight the tighter binding of selective ligands to the proteins compared to non-selective and inactive ligands.<\/jats:p>","DOI":"10.3390\/molecules28196909","type":"journal-article","created":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T11:56:49Z","timestamp":1696247809000},"page":"6909","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Molecular Dynamics Simulation Study of the Selective Inhibition of Coagulation Factor IXa over Factor Xa"],"prefix":"10.3390","volume":"28","author":[{"given":"Hyun Jung","family":"Yoon","sequence":"first","affiliation":[{"name":"Department of Physics, Pukyong National University, Busan 48513, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sibsankar","family":"Kundu","sequence":"additional","affiliation":[{"name":"R&D Center, PharmCADD Co., Ltd., Busan 48792, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5794-9477","authenticated-orcid":false,"given":"Sangwook","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Physics, Pukyong National University, Busan 48513, Republic of Korea"},{"name":"R&D Center, PharmCADD Co., Ltd., Busan 48792, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3799","DOI":"10.1021\/acs.jmedchem.7b00772","article-title":"Design of Small-Molecule Active-Site Inhibitors of the S1A Family Proteases as Procoagulant and Anticoagulant Drugs","volume":"61","author":"Fischer","year":"2018","journal-title":"J. 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