{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T01:37:52Z","timestamp":1763429872835,"version":"build-2065373602"},"reference-count":53,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T00:00:00Z","timestamp":1682035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"FAPESP","doi-asserted-by":"publisher","award":["2017\/20291-0","p2017\/19942-7","2003\/10516-2","309271\/2022-3"],"award-info":[{"award-number":["2017\/20291-0","p2017\/19942-7","2003\/10516-2","309271\/2022-3"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"CNPq","doi-asserted-by":"publisher","award":["2017\/20291-0","p2017\/19942-7","2003\/10516-2","309271\/2022-3"],"award-info":[{"award-number":["2017\/20291-0","p2017\/19942-7","2003\/10516-2","309271\/2022-3"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Snake venom serine protease (SVSP) interferes with the regulation and control of important biological reactions in homeostasis and can be classified as an activator of the fibrinolytic system and platelet aggregation. Our group has recently isolated a new serine protease from Crotalus durissus terrificus total venom (Cdtsp-2). This protein exhibits edematogenic capacity and myotoxic activity. A Kunitz-like EcTI inhibitor protein with a molecular mass of 20 kDa was isolated from Enterolobium contortisiliquum and showed high trypsin inhibition. Thus, the objective of this work is to verify the possible inhibition of the pharmacological activities of Cdtsp-2 by the Kutinz-type inhibitor EcTI. To isolate Cdtsp-2 from total C. d. terrificus venom, we used three-step chromatographic HPLC. Using the mice paw edema model, we observed an edematogenic effect, myotoxicity and hepatotoxicity caused by Cdtsp-2. In vitro and in vivo experiments showed that the alterations in hemostasis caused by Cdtsp-2 are crucial for the development of marked hepatotoxicity and that EcTI significantly inhibits the enzymatic and pharmacological activities of Cdtsp-2. Kunitz-like inhibitor may be a viable alternative for the development of ancillary treatments against the biological activities of venoms.<\/jats:p>","DOI":"10.3390\/ph16040632","type":"journal-article","created":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T06:54:19Z","timestamp":1682060059000},"page":"632","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The First Anti-Snakebite and Hepatoprotective Characterization of a Trypsin Kunitz-like Inhibitor (EcTI) from the Plant Enterolobium contortisiliquum; A Case of Two Soul Mates Meeting"],"prefix":"10.3390","volume":"16","author":[{"given":"Caroline R. C.","family":"Costa","sequence":"first","affiliation":[{"name":"Center of Natural and Human Sciences, Federal University of ABC (UFABC), Santo Andr\u00e9 09210-580, SP, Brazil"},{"name":"Biosciences Institute of Paulista Coast Campus (IB\/CLP), University of S\u00e3o Paulo State (UNESP), S\u00e3o Vicente 11330-900, SP, Brazil"}]},{"given":"Mariana N.","family":"Belchor","sequence":"additional","affiliation":[{"name":"Center of Natural and Human Sciences, Federal University of ABC (UFABC), Santo Andr\u00e9 09210-580, SP, Brazil"},{"name":"Biosciences Institute of Paulista Coast Campus (IB\/CLP), University of S\u00e3o Paulo State (UNESP), S\u00e3o Vicente 11330-900, SP, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4546-8013","authenticated-orcid":false,"given":"Airam","family":"Roggero","sequence":"additional","affiliation":[{"name":"Biosciences Institute of Paulista Coast Campus (IB\/CLP), University of S\u00e3o Paulo State (UNESP), S\u00e3o Vicente 11330-900, SP, Brazil"}]},{"given":"Laila L.","family":"Moraes","sequence":"additional","affiliation":[{"name":"Biosciences Institute of Paulista Coast Campus (IB\/CLP), University of S\u00e3o Paulo State (UNESP), S\u00e3o Vicente 11330-900, SP, Brazil"}]},{"given":"Ricardo","family":"Samelo","sequence":"additional","affiliation":[{"name":"Biosciences Institute of Paulista Coast Campus (IB\/CLP), University of S\u00e3o Paulo State (UNESP), S\u00e3o Vicente 11330-900, SP, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7884-6768","authenticated-orcid":false,"given":"Isabelly","family":"Annunciato","sequence":"additional","affiliation":[{"name":"Biosciences Institute of Paulista Coast Campus (IB\/CLP), University of S\u00e3o Paulo State (UNESP), S\u00e3o Vicente 11330-900, SP, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9324-8424","authenticated-orcid":false,"given":"Camila R.","family":"Bonturi","sequence":"additional","affiliation":[{"name":"National Institute of Pharmacology (INFAR), Federal University of S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo 04044-020, SP, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7346-6328","authenticated-orcid":false,"given":"Maria L. V.","family":"Oliva","sequence":"additional","affiliation":[{"name":"National Institute of Pharmacology (INFAR), Federal University of S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo 04044-020, SP, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6560-5284","authenticated-orcid":false,"given":"Sergio F.","family":"Sousa","sequence":"additional","affiliation":[{"name":"Unit of Applied Biomolecular Sciences (UCIBIO), REQUIMTE-BioSIM-Medicine Faculty, Porto University, 4050-345 Porto, Portugal"}]},{"given":"Marcos A.","family":"de Oliveira","sequence":"additional","affiliation":[{"name":"Center of Natural and Human Sciences, Federal University of ABC (UFABC), Santo Andr\u00e9 09210-580, SP, Brazil"},{"name":"Biosciences Institute of Paulista Coast Campus (IB\/CLP), University of S\u00e3o Paulo State (UNESP), S\u00e3o Vicente 11330-900, SP, Brazil"}]},{"given":"Marcos H.","family":"Toyama","sequence":"additional","affiliation":[{"name":"Center of Natural and Human Sciences, Federal University of ABC (UFABC), Santo Andr\u00e9 09210-580, SP, Brazil"},{"name":"Biosciences Institute of Paulista Coast Campus (IB\/CLP), University of S\u00e3o Paulo State (UNESP), S\u00e3o Vicente 11330-900, SP, Brazil"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e20200066","DOI":"10.1590\/1678-9199-jvatitd-2020-0066","article-title":"Design, synthesis, and evaluation of Bothrops venom serine protease peptidic inhibitors","volume":"27","author":"Waitman","year":"2021","journal-title":"J. Venom. Anim. Toxins Incl. Trop. Dis."},{"key":"ref_2","unstructured":"Moio Da Cunha, E., and Martins, O.A. (2023, January 12). Principais Compostos Qu\u00edmicos Presente nos Venenos de Cobras dos G\u00eaneros Bothrops e Crotalus-Uma Revis\u00e3o. 2012, 2, 21\u201326. Available online: www.scielo.br."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.molcel.2011.08.040","article-title":"Peroxiredoxin II Is an Essential Antioxidant Enzyme that Prevents the Oxidative Inactivation of VEGF Receptor-2 in Vascular Endothelial Cells","volume":"44","author":"Kang","year":"2011","journal-title":"Mol. Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.2174\/0929867324666170605091546","article-title":"Snake Venom: From Deadly Toxins to Life-saving Therapeutics","volume":"24","author":"Waheed","year":"2017","journal-title":"Curr. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1590\/S0100-879X2002001000016","article-title":"Evaluation of Antivenoms in the Neutralization of Hyperalgesia and Edema Induced by Bothrops Jararaca and Bothrops Asper Snake Venoms","volume":"35","author":"Picolo","year":"2002","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_6","unstructured":"Miyagui, C., and Brando Prieto da Silva lvaro R de Santana, G. (2013). An Integrated View of the Molecular Recognition and Toxinology\u2014From Analytical Procedures to Biomedical Applications, IntechOpen."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1590\/S0037-86821989000100002","article-title":"A Retrospective Study of 40 Victims of Crotalus Snake Bites: Analysis of the Hepatic Necrosis Observed in One Patient","volume":"22","author":"Barraviera","year":"1989","journal-title":"Rev Soc Bras Med. Trop"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1016\/0041-0101(93)90124-2","article-title":"Toxins as tools in the study of sodium channel distribution in the muscle fibre membrane","volume":"31","author":"Fontana","year":"1993","journal-title":"Toxicon Off. J. Int. Soc. Toxinology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1590\/S0036-46651994000500015","article-title":"Acute-phase response in snakebite","volume":"36","author":"Barraviera","year":"1994","journal-title":"Rev. Inst. Med. Trop. S\u00e3o Paulo"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1016\/j.febslet.2009.03.029","article-title":"Venoms, venomics, antivenomics","volume":"583","author":"Calvete","year":"2009","journal-title":"FEBS Lett."},{"key":"ref_11","first-page":"61","article-title":"Acute hepatotoxicity of Crotalus durissus terrificus (South American rattlesnake) venom in rats","volume":"13","author":"Ral","year":"2008","journal-title":"J. Venom. Anim.Toxins Incl. Trop. Dis. V"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Costa, C.R.C., Belchor, M.N., Rodrigues, C.F.B., Toyama, D.D.O., De Oliveira, M.A., Novaes, D.P., and Toyama, M.H. (2018). Edema Induced by a Crotalus durissus terrificus Venom Serine Protease (Cdtsp 2) Involves the PAR Pathway and PKC and PLC Activation. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19082405"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"G171","DOI":"10.1152\/ajpgi.00402.2017","article-title":"Role of the blood coagulation cascade in hepatic fibrosis","volume":"315","author":"Pant","year":"2018","journal-title":"Am. J. Physiol. Gastrointest. Liver. Physiol."},{"key":"ref_14","unstructured":"Costa, C.R.C. (2023, March 14). Avalia\u00e7\u00e3o de Compostos Polifen\u00f3licos da Laguncularia Racemosa Sobre a Atividade Enzim\u00e1tica e Farmacol\u00f3gica de Serino Proteases de Crotalus durissus terrificus. 22 February 2018. Available online: https:\/\/repositorio.unesp.br\/handle\/11449\/153268."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1107\/S0907444901001810","article-title":"Preliminary crystallographic studies of EcTI, a serine proteinase inhibitor from Enterolobium contortisiliquum seeds","volume":"57","author":"Batista","year":"2001","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.canlet.2020.08.017","article-title":"EcTI impairs survival and proliferation pathways in triple-negative breast cancer by modulating cell-glycosaminoglycans and inflammatory cytokines","volume":"491","author":"Lobo","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhou, D., Lobo, Y.A., Batista, I.F.C., Marques-Porto, R., Gustchina, A., Oliva, M.L.V., and Wlodawer, A. (2013). Crystal Structures of a Plant Trypsin Inhibitor from Enterolobium contortisiliquum (EcTI) and of Its Complex with Bovine Trypsin. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0062252"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1055\/s-0038-1657717","article-title":"Inhibition of thrombin generation in plasma by inhibitors of factor Xa","volume":"78","author":"Prasa","year":"1997","journal-title":"Thromb Haemost"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1002\/tox.22660","article-title":"Prepubertal exposure to low doses of sodium arsenite impairs spermatogenesis and epididymal histophysiology in rats","volume":"34","author":"Samelo","year":"2019","journal-title":"Environ Toxicol."},{"key":"ref_20","unstructured":"Society of Toxicology Pathology (2018, December 10). Standardized System of Nomenclature and Diagnostic Criteria (SSNDC) Guides. Available online: https:\/\/www.toxpath.org\/ssndc.asp."},{"key":"ref_21","unstructured":"(2018, December 10). National Toxicology Program Health and Human Services. Guides, Available online: https:\/\/ntp.niehs.nih.gov\/nnl\/hepatobiliary\/liver\/fatty_change\/index.htm#group-5."},{"key":"ref_22","first-page":"185","article-title":"Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism","volume":"187","author":"Mitchell","year":"1973","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4505","DOI":"10.3390\/md13074505","article-title":"Evaluation of Potential Thrombin Inhibitors from the White Mangrove (Laguncularia racemosa (L.) C.F. Gaertn)","volume":"13","author":"Rodrigues","year":"2015","journal-title":"Mar. Drugs"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1111\/j.2042-7158.1972.tb08940.x","article-title":"Biological Properties of Carrageenan","volume":"24","year":"2011","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.intimp.2013.02.023","article-title":"Effects of two serine proteases from Bothrops pirajai snake venom on the complement system and the inflammatory response","volume":"15","author":"Menaldo","year":"2013","journal-title":"Int. Immunopharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e001508","DOI":"10.1161\/JAHA.114.001508","article-title":"Effect of extended-release niacin on high-density lipoprotein (HDL) functionality, lipoprotein metabolism, and mediators of vascular inflammation in statin-treated patients","volume":"4","author":"Yadav","year":"2015","journal-title":"J Am Heart Assoc"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1111\/jdv.18779","article-title":"Real-World Outcomes Using PD-1 Antibodies and BRAF + MEK Inhibitors for Adjuvant Melanoma Treatment from 39 Skin Cancer Centers in Germany, Austria and Switzerland","volume":"37","author":"Schumann","year":"2022","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1183\/09031936.96.09081736","article-title":"Usefulness of Lactate Dehydrogenase and Its Isoenzymes as Indicators of Lung Damage or Inflammation","volume":"9","author":"Drent","year":"1996","journal-title":"Eur. Respir. J."},{"key":"ref_29","unstructured":"Farhana, A., and Lappin, S.L. (2022). Biochemistry, Lactate Dehydrogenase. StatPearls, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK557536\/."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/1678-9199-20-42","article-title":"Hepatotoxicity and oxidative stress induced by Naja hajecrude venom","volume":"20","author":"Dkhil","year":"2014","journal-title":"J. Venom. Anim. Toxins Incl. Trop. Dis."},{"key":"ref_31","first-page":"21","article-title":"Clinica chimica acta 293 a routine procedure for estimating serum y-glutamyl-transpeptidase activity","volume":"258","author":"Naftalin","year":"1997","journal-title":"Clin. Chim. Acta"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1111\/liv.15239","article-title":"Disease burden and management of Crigler-Najjar syndrome: Report of a world registry","volume":"42","author":"Aronson","year":"2022","journal-title":"Liver Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"367","DOI":"10.2147\/NDT.S156710","article-title":"Oxidative\/antioxidative status, lymphocyte DNA damage, and urotensin-2 receptor level in patients with migraine attacks","volume":"14","author":"Yigit","year":"2018","journal-title":"Neuropsychiatr. Dis. Treat"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1177\/0300985816641994","article-title":"Veterinary Forensic Toxicology","volume":"53","year":"2016","journal-title":"Vet Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1017\/S0007114514002554","article-title":"Astaxanthin Lowers Plasma TAG Concentrations and Increases Hepatic Antioxidant Gene Expression in Diet-Induced Obesity Mice","volume":"112","author":"Yang","year":"2014","journal-title":"Br. J. Nutr."},{"key":"ref_36","first-page":"817","article-title":"The Past and Present of Serum Aminotransferases and the Future of Liver Injury Biomarkers","volume":"15","author":"McGill","year":"2016","journal-title":"EXCLI J."},{"key":"ref_37","unstructured":"Thomas Francis, J. (1936). Biographical Memoirs: Volume 44-National Academy of Sciences-Google Livros, Rock & Read Books Publishing Company."},{"key":"ref_38","first-page":"237","article-title":"C Reactive Protein","volume":"65","author":"Nehring","year":"2017","journal-title":"StatPearls"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6370","DOI":"10.1074\/jbc.272.10.6370","article-title":"Hepatocyte Growth Factor Activator Inhibitor, a Novel Kunitz-Type Serine Protease Inhibitor","volume":"272","author":"Shimomura","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"23188","DOI":"10.1074\/jbc.M116.732743","article-title":"Targeting Liver Fibrosis with a Cell-Penetrating Protease-Activated Receptor-2 (PAR2) Pepducin","volume":"291","author":"Shearer","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1016\/j.biochi.2010.03.021","article-title":"A novel subclassification for Kunitz proteinase inhibitors from leguminous seeds","volume":"92","author":"Oliva","year":"2010","journal-title":"Biochimie"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.toxicon.2011.11.001","article-title":"Angiotensin-degrading serine peptidase: A new chymotrypsin-like activity in the venom of Bothrops jararaca partially blocked by the commercial antivenom","volume":"59","author":"Kuniyoshi","year":"2012","journal-title":"Toxicon"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1038\/sj.emboj.7600611","article-title":"The Many Faces of Protease\u2013Protein Inhibitor Interaction","volume":"24","author":"Otlewski","year":"2005","journal-title":"EMBO J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2361","DOI":"10.1002\/j.1460-2075.1990.tb07410.x","article-title":"Crystal Structure of the Thrombin-Hirudin Complex: A Novel Mode of Serine Protease Inhibition","volume":"9","author":"Priestle","year":"1990","journal-title":"EMBO J."},{"key":"ref_45","unstructured":"Richardson, L. (2023, March 15). Turning Points in Qualitative Research: Tying Knots in a Handkerchief-Google Livros. Available online: https:\/\/books.google.com.br\/books?hl=pt-BR&lr=&id=8aXWAQAAQBAJ&oi=fnd&pg=PA379&dq=Writing+a+method+of+inquiry&ots=lhcYI-FNKx&sig=XXfeR0Yi77HNo2OuMuzujUSvKas&redir_esc=y#v=onepage&q=Writing%20a%20method%20of%20inquiry&f=false."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"W374","DOI":"10.1093\/nar\/gky380","article-title":"CavityPlus: A web server for protein cavity detection with pharmacophore modelling, allosteric site identification and covalent ligand binding ability prediction","volume":"46","author":"Xu","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e18482","DOI":"10.1590\/s2175-97902019000418482","article-title":"Effects of treatment with sitagliptin on hepatotoxicity induced by acetaminophen in mice","volume":"56","author":"Hewedy","year":"2021","journal-title":"Braz. J. Pharm. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/(SICI)1099-1352(199601)9:1<1::AID-JMR241>3.0.CO;2-6","article-title":"Automated Docking of Flexible Ligands: Applications of AutoDock","volume":"9","author":"Goodsell","year":"1996","journal-title":"J. Mol. Recognit."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s10930-006-9001-z","article-title":"Charcterization of a new platelet aggregating factor from crotoxin Crotalus durissus cascavella venom","volume":"25","author":"Fonseca","year":"2006","journal-title":"Protein J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1021\/ci800324m","article-title":"Identifying and characterizing binding sites and assessing druggability","volume":"49","author":"Halgren","year":"2009","journal-title":"J. Chem. Inf. Model."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1093\/protein\/8.2.127","article-title":"LIGPLOT: A Program to Generate Schematic Diagrams of Protein-Ligand Interactions","volume":"8","author":"Wallace","year":"1995","journal-title":"Protein Eng. Des. Sel."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/4\/632\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:20:38Z","timestamp":1760124038000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/4\/632"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,21]]},"references-count":53,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ph16040632"],"URL":"https:\/\/doi.org\/10.3390\/ph16040632","relation":{},"ISSN":["1424-8247"],"issn-type":[{"type":"electronic","value":"1424-8247"}],"subject":[],"published":{"date-parts":[[2023,4,21]]}}}