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In this paper, the binding modes and inhibitory mechanisms of four 7H-pyrrolo[2,3-d]pyrimidine competitive inhibitors of PAK4 were investigated at the molecular level, mainly using molecular dynamics simulations and binding free energy calculations. The results show that the inhibitors had strong interactions with the hinge region, the \u03b2-sheets, and the residues with charged side chains around the 4-substituent. The terminal amino group of the inhibitor 5n was different from the other three, which could cause the enhancement of hydrogen bonds or electrostatic interactions formed with the surrounding residues. Thus, inhibitor 5n had the strongest inhibition capacity. The different halogen atoms on the 2-substituents of the inhibitors 5h, 5g, and 5e caused differences in the positions of the 2-benzene rings and affected the interactions of the hinge region. It also affected to some extent the orientations of the 4-imino groups and consequently their affinities for the surrounding charged residues. The combined results lead to the weakest inhibitory capacity of inhibitor 5e.<\/jats:p>","DOI":"10.3390\/molecules28010413","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T02:54:55Z","timestamp":1672800895000},"page":"413","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Inhibitory Mechanism of 7H-Pyrrolo[2,3-d]pyrimidine Derivatives as Inhibitors of P21-Activated Kinase 4 through Molecular Dynamics Simulation"],"prefix":"10.3390","volume":"28","author":[{"given":"Juan","family":"Du","sequence":"first","affiliation":[{"name":"Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yurou","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"59","DOI":"10.4161\/cl.21912","article-title":"PAK family kinases: Physiological roles and regulation","volume":"2","author":"Zhao","year":"2012","journal-title":"Cell Logist."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1186\/s12935-022-02689-6","article-title":"Comprehensive analysis of the prognostic implications and functional exploration of PAK gene family in human cancer","volume":"22","author":"Lei","year":"2022","journal-title":"Cancer Cell Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e28003","DOI":"10.4161\/sgtp.28003","article-title":"P21 activated kinases: Structure, regulation, and functions","volume":"5","author":"Rane","year":"2014","journal-title":"Small GTPases"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"579","DOI":"10.2217\/fon-2017-0458","article-title":"PAK4 pathway as a potential therapeutic target in pancreatic cancer","volume":"14","author":"Thillai","year":"2018","journal-title":"Future Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.3748\/wjg.v22.i3.1224","article-title":"Group II p21-activated kinases as therapeutic targets in gastrointestinal cancer","volume":"22","author":"Shao","year":"2016","journal-title":"World J. 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