{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T16:48:39Z","timestamp":1774370919702,"version":"3.50.1"},"reference-count":81,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T00:00:00Z","timestamp":1706486400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Cellular Biochemistry"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Human transmembrane serine protease 2 (TMPRSS2) is an important member of the type 2 transmembrane serine protease (TTSP) family with significant therapeutic markings. The search for potent TMPRSS2 inhibitors against severe acute respiratory syndrome coronavirus 2 infection with favorable tissue specificity and off\u2010site toxicity profiles remains limited. Therefore, probing the anti\u2010TMPRSS2 potential of enhanced drug delivery systems, such as nanotechnology and prodrug systems, has become compelling. We report the first in silico study of TMPRSS2 against a prodrug, [isopropyl(S)\u20102\u2010((S)\u20102\u2010acetamido\u20103\u2010(1H\u2010indol\u20103\u2010yl)\u2010propanamido)\u20106\u2010diazo\u20105\u2010oxo\u2010hexanoate] also known as DRP\u2010104 synthesized from 6\u2010Diazo\u20105\u2010oxo\u2010<jats:sc>l<\/jats:sc>\u2010norleucine (DON). We performed comparative studies on DON and DRP\u2010104 against a clinically potent TMPRSS2 inhibitor, nafamostat, and a standard serine protease inhibitor, 4\u2010(2\u2010Aminoethyl) benzenesulfonyl fluoride (AEBSF) against TMPRSS2 and found improved TMPRSS2 inhibition through synergistic binding of the S1\/S1' subdomains. Both DON and DRP\u2010104 had better thermodynamic profiles than AEBSF and nafamostat. DON was found to confer structural stability with strong positive correlated inter\u2010residue motions, whereas DRP\u2010104 was found to confer kinetic stability with restricted residue displacements and reduced loop flexibility. Interestingly, the Scavenger Receptor Cysteine\u2010Rich (SRCR) domain of TMPRSS2 may be involved in its inhibition mechanics. Two previously unidentified loops, designated X (270\u2212275) and Y (293\u2212296) underwent minimal and major structural transitions, respectively. In addition, residues 273\u2212277 consistently transitioned to a turn conformation in all ligated systems, whereas unique transitions were identified for other transitioning residue groups in each TMPRSS2\u2010inhibitor complex. Intriguingly, while both DON and DRP\u2010104 showed similar loop transition patterns, DRP\u2010104 preserved loop structural integrity. As evident from our systematic comparative study using experimentally\/clinically validated inhibitors, DRP\u2010104 may serve as a potent and novel TMPRSS2 inhibitor and warrants further clinical investigation.<\/jats:p>","DOI":"10.1002\/jcb.30528","type":"journal-article","created":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T10:09:52Z","timestamp":1706522992000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["DON\/DRP\u2010104 as potent serine protease inhibitors implicated in SARS\u2010CoV\u20102 infection: Comparative binding modes with human TMPRSS2 and novel therapeutic approach"],"prefix":"10.1002","volume":"125","author":[{"given":"Ernest","family":"Oduro\u2010Kwateng","sequence":"first","affiliation":[{"name":"School of Health Sciences, Molecular Bio\u2010Computation and Drug Design Research Group, Westville Campus University of KwaZulu Natal Durban South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8711-7783","authenticated-orcid":false,"given":"Mahmoud E.","family":"Soliman","sequence":"additional","affiliation":[{"name":"School of Health Sciences, Molecular Bio\u2010Computation and Drug Design Research Group, Westville Campus University of KwaZulu Natal Durban South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,1,29]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/iub.186"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1110\/ps.035436.108"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-005-5160-x"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/453186"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-10-3162-5_10"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S285852"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpclett.2c00967"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2019.1632639"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.832418"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201948270"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav2588"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00649-19"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00124-15"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2020.04.022"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-021-00418-x"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2002589117"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.090665"},{"issue":"4","key":"e_1_2_8_19_1","first-page":"410","article-title":"Association between TMPRSS2:ERG fusion gene and the prostate cancer: systematic review and meta\u2010analysis","volume":"71","author":"Garc\u00eda\u2010Perdomo HA","year":"2018","journal-title":"Cent European J Urol"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27426"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s43440-022-00394-9"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.725528"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/s44149-023-00075-x"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-022-01059-7"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33911-8"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/v15020271"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2007764"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.671263"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2020.110668"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jiph.2020.07.004"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.111330"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1039\/D0SC05064D"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.26397"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/v12060629"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20130101"},{"key":"e_1_2_8_36_1","doi-asserted-by":"crossref","unstructured":"BojkovaD McGreigJ McLaughlinK\u2010M et al. 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