{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T01:59:16Z","timestamp":1785376756143,"version":"3.55.0"},"reference-count":49,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    HIV\u20101 protease (HIV\u20101 PR) is a critical therapeutic target for HIV treatment, yet the development of novel inhibitors with improved efficacy remains a significant challenge. This study investigates the molecular mechanisms underlying the binding of three diastereoisomers of the novel phosphinate pseudopeptide inhibitor PAC\u2010Phe\u2010Val (\n                    <jats:italic>SSSS<\/jats:italic>\n                    ,\n                    <jats:italic>SRSS<\/jats:italic>\n                    ,\n                    <jats:italic>SRRS<\/jats:italic>\n                    ) to HIV\u20101 PR in comparison with Darunavir, a clinically approved inhibitor. Using molecular dynamics simulations and MM\/PBSA calculations, we characterized protein stability, flap dynamics, and allosteric communication networks within the protease\u2010inhibitor complexes. Our results revealed that the\n                    <jats:italic>SRSS<\/jats:italic>\n                    isomer conferred superior structural stabilization comparable to Darunavir by suppressing global protein flexibility and maintaining a closed, catalytically inactive flap conformation. Importantly,\n                    <jats:italic>SRSS<\/jats:italic>\n                    disrupted key allosteric communication pathways within the protease. MM\/PBSA analysis indicated that\n                    <jats:italic>SRSS<\/jats:italic>\n                    exhibited the highest binding affinity (\u221211.76\u2009kcal\/mol) among the designed inhibitors, driven primarily by a strong salt bridge interaction with the Arg8 residue. However, a substantial solvation penalty limited its overall binding affinity relative to Darunavir (\u221215.75\u2009kcal\/mol). These findings identify\n                    <jats:italic>SRSS<\/jats:italic>\n                    as a promising lead compound for HIV\u20101 PR inhibitor development. Our work provides atomic\u2010level mechanistic insights into inhibitor binding and suggests that future optimization strategies should focus on reducing ligand polarity to minimize desolvation penalties and enhance binding affinity.\n                  <\/jats:p>","DOI":"10.1002\/pro.70611","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T12:25:37Z","timestamp":1778243137000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phosphinate pseudopeptide enhances binding free energy in\n                    <scp>HIV<\/scp>\n                    \u20101 protease by driving flap closure and suppressing global flexibility"],"prefix":"10.1002","volume":"35","author":[{"given":"Yuxin","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Biosciences and Bioinformatics Xi'an Jiaotong\u2010Liverpool University  Suzhou Jiangsu Province People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danwen","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Materials Science Xi'an Jiaotong\u2010Liverpool University  Suzhou Jiangsu Province People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0324-0934","authenticated-orcid":false,"given":"Magdalini","family":"Matziari","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Materials Science Xi'an Jiaotong\u2010Liverpool University  Suzhou Jiangsu Province People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9088-0723","authenticated-orcid":false,"given":"Faez Iqbal","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Bioinformatics Xi'an Jiaotong\u2010Liverpool University  Suzhou Jiangsu Province People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00082a019"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2018.11.016"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.softx.2015.06.001"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.28020"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo0521504"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-62423-y"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0968-0896(95)00069-S"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.2408420"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1128\/aac.49.6.2314-2321.2005"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm201109t"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.1c00203"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00137a016"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/JM051256O"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1517\/17460441.2015.1032936"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291x(90)92010-w"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.saa.2019.117807"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.4c05988"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.5c09361"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.62.8.2587-2595.1988"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0508452103"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00045a067"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-2836(02)00470-9"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtbi.2015.03.035"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.794780"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2022.794960"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmr.2958"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.saa.2021.119572"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1073\/PNAS.85.13.4686"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2015.03.021"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425250903273160"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.22711"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1054-3589(07)55008-8"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.1c00302"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2010.01.020"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2007.07.095"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol0069103"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2026.109572"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm200587f"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.328693"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-7208(97)80081-5"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.199317201"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(01)80327-9"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b00104"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.540151106"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1186\/1756-0500-5-367"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.22.8805"},{"key":"e_1_2_10_48_1","unstructured":"UNAIDS.Global AIDS update 2025: AIDS crisis and the power to transform.2025Retrieved fromhttps:\/\/www.unaids.org\/en\/UNAIDS-global-AIDS-update-2025"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.1c00645"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo9603439"}],"container-title":["Protein Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pro.70611","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/pro.70611","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pro.70611","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T01:34:13Z","timestamp":1785375253000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pro.70611"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,8]]},"references-count":49,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1002\/pro.70611"],"URL":"https:\/\/doi.org\/10.1002\/pro.70611","archive":["Portico"],"relation":{},"ISSN":["0961-8368","1469-896X"],"issn-type":[{"value":"0961-8368","type":"print"},{"value":"1469-896X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,8]]},"assertion":[{"value":"2026-01-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70611"}}