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The development of antiviral drugs primarily aimed at inhibition of proteases required for the proteolysis of viral polyproteins. In this study, the conformation of the pS273R protease in physiological states were investigated, virtually screened the multi-protein conformation of pS273R target proteins, combined various molecular docking scoring functions, and identified five potential drugs from the Food and Drug Administration drug library that may inhibit pS273R. Subsequent validation of the dynamic interactions of pS273R with the five putative inhibitors was achieved using molecular dynamics simulations and binding free energy calculations using the molecular mechanics\/Poison-Boltzmann (Generalized Born) (MM\/PB(GB)SA) surface area. These findings demonstrate that the arm domain and Thr159-Lys167 loop region of pS273R are significantly more flexible compared to the core structural domain, and the Thr159-Lys167 loop region can serve as a \u201cgatekeeper\u201d in the substrate channel. Leucovorin, Carboprost, Protirelin, Flavin Mononucleotide, and Lovastatin Acid all have Gibbs binding free energies with pS273R that were less than \u221220 Kcal\/mol according to the MM\/PBSA analyses. In contrast to pS273R in the free energy landscape, the inhibitor and drug complexes of pS273R showed distinct structural group distributions. These five drugs may be used as potential inhibitors of pS273R and may serve as future drug candidates for treating ASFV.<\/jats:p>","DOI":"10.3390\/molecules28020570","type":"journal-article","created":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T03:19:54Z","timestamp":1672975194000},"page":"570","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Structural Analysis, Multi-Conformation Virtual Screening and Molecular Simulation to Identify Potential Inhibitors Targeting pS273R Proteases of African Swine Fever Virus"],"prefix":"10.3390","volume":"28","author":[{"given":"Gen","family":"Lu","sequence":"first","affiliation":[{"name":"Key Laboratory of Livestock Infectious Diseases, Ministry of Education, Shenyang Agricultural University, No. 120, Dongling Road, Shenhe District, Shenyang 110866, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang","family":"Ou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock Infectious Diseases, Ministry of Education, Shenyang Agricultural University, No. 120, Dongling Road, Shenhe District, Shenyang 110866, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock Infectious Diseases, Ministry of Education, Shenyang Agricultural University, No. 120, Dongling Road, Shenhe District, Shenyang 110866, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock Infectious Diseases, Ministry of Education, Shenyang Agricultural University, No. 120, Dongling Road, Shenhe District, Shenyang 110866, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shouhua","family":"Feng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock Infectious Diseases, Ministry of Education, Shenyang Agricultural University, No. 120, Dongling Road, Shenhe District, Shenyang 110866, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuofeng","family":"Yang","sequence":"additional","affiliation":[{"name":"The Preventive and Control Center of Animal Disease of Liaoning Province, Liaoning Agricultural Development Service Center, No. 95, Renhe Road, Shenbei District, Shenyang 110164, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo","family":"Sun","sequence":"additional","affiliation":[{"name":"Qianyuanhao Biological Co., Ltd., Building 20, District 11, No. 188 South Fourth Ring West Road, Fengtai District, Beijing 100070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinling","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock Infectious Diseases, Ministry of Education, Shenyang Agricultural University, No. 120, Dongling Road, Shenhe District, Shenyang 110866, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Wei","sequence":"additional","affiliation":[{"name":"The Preventive and Control Center of Animal Disease of Liaoning Province, Liaoning Agricultural Development Service Center, No. 95, Renhe Road, Shenbei District, Shenyang 110164, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shude","family":"Pan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock Infectious Diseases, Ministry of Education, Shenyang Agricultural University, No. 120, Dongling Road, Shenhe District, Shenyang 110866, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeliang","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock Infectious Diseases, Ministry of Education, Shenyang Agricultural University, No. 120, Dongling Road, Shenhe District, Shenyang 110866, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Karger, A., Perez-Nunez, D., Urquiza, J., Hinojar, P., Alonso, C., Freitas, F.B., Revilla, Y., Le Potier, M.F., and Montoya, M. 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