{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T15:35:09Z","timestamp":1791041709017,"version":"4.1.0"},"reference-count":65,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,12,20]],"date-time":"2019-12-20T00:00:00Z","timestamp":1576800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005278","name":"Universidad de Antioquia","doi-asserted-by":"publisher","award":["CODI-CIQF-217"],"award-info":[{"award-number":["CODI-CIQF-217"]}],"id":[{"id":"10.13039\/501100005278","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["CHE-1726332"],"award-info":[{"award-number":["CHE-1726332"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Snake bite envenoming is a public health problem that was recently included in the list of neglected tropical diseases of the World Health Organization. In the search of new therapies for the treatment of local tissue damage induced by snake venom metalloproteinases (SVMPs), we tested the inhibitory activity of peptidomimetic compounds designed as inhibitors of matrix metalloproteinases on the activities of the SVMP Batx-I, from Bothrops atrox venom. The evaluated compounds show great potential for the inhibition of Batx-I proteolytic, hemorrhagic and edema-forming activities, especially the compound CP471474, a peptidomimetic including a hydroxamate zinc binding group. Molecular dynamics simulations suggest that binding of this compound to the enzyme is mediated by the electrostatic interaction between the hydroxamate group and the zinc cofactor, as well as contacts, mainly hydrophobic, between the side chain of the compound and amino acids located in the substrate binding subsites S1 and S1     \u2032    . These results show that CP471474 constitutes a promising compound for the development of co-adjuvants to neutralize local tissue damage induced by snake venom metalloproteinases.<\/jats:p>","DOI":"10.3390\/toxins12010008","type":"journal-article","created":{"date-parts":[[2019,12,23]],"date-time":"2019-12-23T03:23:12Z","timestamp":1577071392000},"page":"8","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Potential of Matrix Metalloproteinase Inhibitors for the Treatment of Local Tissue Damage Induced by a Type P-I Snake Venom Metalloproteinase"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3096-2134","authenticated-orcid":false,"given":"Lina Mar\u00eda","family":"Preciado","sequence":"first","affiliation":[{"name":"Programa de Ofidismo\/Escorpionismo, Facultad de Ciencias Farmac\u00e9uticas y Alimentarias, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medell\u00edn 050010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9612-2827","authenticated-orcid":false,"given":"Jaime Andr\u00e9s","family":"Perea\u00f1ez","sequence":"additional","affiliation":[{"name":"Programa de Ofidismo\/Escorpionismo, Facultad de Ciencias Farmac\u00e9uticas y Alimentarias, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medell\u00edn 050010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4437-1260","authenticated-orcid":false,"given":"Jeffrey","family":"Comer","sequence":"additional","affiliation":[{"name":"Institute of Computational Comparative Medicine, Kansas State University, Manhattan, KS 66506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s40409-017-0127-6","article-title":"Snakebite envenomation turns again into a neglected tropical disease!","volume":"23","author":"Chippaux","year":"2017","journal-title":"J. Venom. Anim. Toxins Incl. Trop. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Chippaux, J.P. (2017). Incidence and mortality due to snakebite in the Americas. PLoS Negl. Trop. Dis., 11.","DOI":"10.1371\/journal.pntd.0005662"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"17063","DOI":"10.1038\/nrdp.2017.63","article-title":"Snakebite envenoming","volume":"3","author":"Calvete","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","unstructured":"(2019, December 16). Informe Final de Accidente of\u00eddico Colombia a\u00f1o 2018, Available online: https:\/\/www.ins.gov.co\/buscador-eventos\/Informesdeevento\/ACCIDENTE%20OF%C3%8DDICO_2018.pdf."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1016\/j.toxicon.2009.07.001","article-title":"Epidemiological, clinical and therapeutic aspects of Bothrops asper bites","volume":"54","year":"2009","journal-title":"Toxicon"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/j.toxicon.2009.01.038","article-title":"Experimental pathology of local tissue damage induced by Bothrops asper snake venom","volume":"54","author":"Rucavado","year":"2009","journal-title":"Toxicon"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1586\/14789450.5.6.787","article-title":"Proteome analysis of snake venom toxins: Pharmacological insights","volume":"5","author":"Georgieva","year":"2008","journal-title":"Exp. Rev. Proteomic"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/0014-5793(93)80312-I","article-title":"Astacins, serralysins, snake venom and matrix metalloproteinases exhibit identical zinc-binding environments (HEXXHXXGXXH and Met-turn) and topologies and should be grouped into a common family, the \u2018metzincins\u2019","volume":"331","author":"Bode","year":"1993","journal-title":"FEBS Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3016","DOI":"10.1111\/j.1742-4658.2008.06466.x","article-title":"Insights into and speculations about snake venom metalloproteinase (SVMP) synthesis, folding and disulfide bond formation and their contribution to venom complexity","volume":"275","author":"Fox","year":"2008","journal-title":"FEBS J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6166","DOI":"10.1021\/bi9002315","article-title":"High-resolution crystal structure of the snake venom metalloproteinase BaP1 complexed with a peptidomimetic: Insight into inhibitor binding","volume":"48","author":"Lingott","year":"2009","journal-title":"Biochemistry"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3556","DOI":"10.1021\/pr800332p","article-title":"Snake venomics of the lancehead pitviper Bothrops asper: Geographic, individual, and ontogenetic variations","volume":"7","author":"Sanz","year":"2008","journal-title":"J. Proteome Res."},{"key":"ref_12","first-page":"249","article-title":"Mapping the active site of papain with the aid of peptide substrates and inhibitors","volume":"257","author":"Berger","year":"1970","journal-title":"Proc. R. Soc. Lond. B. (Biol. Sci.)"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Gupta, S.P., and Patil, V.M. (2012). Specificity of binding with matrix metalloproteinases. Matrix Metalloproteinase Inhibitors, Springer.","DOI":"10.1007\/978-3-0348-0364-9"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Guti\u00e9rrez, J., Escalante, T., Rucavado, A., and Herrera, C. (2016). Hemorrhage caused by snake venom metalloproteinases: A journey of discovery and understanding. Toxins, 8.","DOI":"10.3390\/toxins8040093"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/S0300-9084(00)01163-9","article-title":"Snake venom metalloproteinases: Their role in the pathogenesis of local tissue damage","volume":"82","author":"Rucavado","year":"2000","journal-title":"Biochimie"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1016\/S0041-0101(98)00145-7","article-title":"Neutralization of local tissue damage induced by Bothrops asper (terciopelo) snake venom","volume":"36","author":"Rojas","year":"1998","journal-title":"Toxicon"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Lancet (2019). Snakebite\u2014Emerging from the shadows of neglect. Lancet, 393, 2175.","DOI":"10.1016\/S0140-6736(19)31232-2"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Rasmussen, H.S. (1999). Batimastat and Marimastat in Cancer. Antiangiogenic Agents in Cancer Therapy, Springer.","DOI":"10.1007\/978-1-59259-453-5_23"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S0006-2952(00)00302-6","article-title":"Effectiveness of batimastat, a synthetic inhibitor of matrix metalloproteinases, in neutralizing local tissue damage induced by BaP1, a hemorrhagic metalloproteinase from the venom of the snake Bothrops asper","volume":"60","author":"Escalante","year":"2000","journal-title":"Biochem. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.toxicon.2004.01.016","article-title":"Effect of the metalloproteinase inhibitor batimastat in the systemic toxicity induced by Bothrops asper snake venom: Understanding the role of metalloproteinases in envenomation","volume":"43","author":"Rucavado","year":"2004","journal-title":"Toxicon"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.toxicon.2017.04.001","article-title":"Peptidomimetic hydroxamate metalloproteinase inhibitors abrogate local and systemic toxicity induced by Echis ocellatus (saw-scaled) snake venom","volume":"132","author":"Arias","year":"2017","journal-title":"Toxicon"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1006\/bbrc.1994.1392","article-title":"Inhibition of matrix metalloproteinases by peptidyl hydroxamic acids","volume":"199","author":"Odake","year":"1994","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.1016\/j.bmc.2004.01.047","article-title":"New N-arylsulfonyl-N-alkoxyaminoacetohydroxamic acids as selective inhibitors of gelatinase A (MMP-2)","volume":"12","author":"Rossello","year":"2004","journal-title":"Bioorg. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3063","DOI":"10.1161\/01.CIR.99.23.3063","article-title":"Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice","volume":"99","author":"Rohde","year":"1999","journal-title":"Circulation"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/S0076-6879(76)45058-9","article-title":"Structures and activities of protease inhibitors of microbial origin","volume":"Volume 45","author":"Umezawa","year":"1976","journal-title":"Methods in Enzymology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1248\/cpb.39.1489","article-title":"Vertebrate collagenase inhibitor. II. Tetrapeptidyl hydroxamic acids","volume":"39","author":"Odake","year":"1991","journal-title":"Chem. Pharm. Bull."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.ejmech.2012.10.016","article-title":"Sulphonamides: Deserving class as MMP inhibitors?","volume":"60","author":"Jain","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1378\/chest.123.5.1633","article-title":"Matrix metalloproteinases inhibition attenuates tobacco smoke-induced emphysema in guinea pigs","volume":"123","author":"Selman","year":"2003","journal-title":"Chest"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Van den Burg, B., and Eijsink, V. (2004). Thermolysin and related Bacillus metallopeptidases. Handbook of Proteolytic Enzymes, Elsevier.","DOI":"10.1016\/B978-0-12-079611-3.50102-6"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"621","DOI":"10.7164\/antibiotics.26.621","article-title":"A thermolysin inhibitor produced by actinomycetes: Phosphoramidon","volume":"26","author":"Suda","year":"1973","journal-title":"J. Antibiot."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/0163-7258(94)90049-3","article-title":"Hemorrhagic metalloproteinases from snake venoms","volume":"62","author":"Bjarnason","year":"1994","journal-title":"Pharmacol. Therapeut."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/j.toxicon.2010.06.016","article-title":"Isolation and biological characterization of Batx-I, a weak hemorrhagic and fibrinogenolytic PI metalloproteinase from Colombian Bothrops atrox venom","volume":"56","author":"Benjumea","year":"2010","journal-title":"Toxicon"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.cbi.2017.12.001","article-title":"Betulinic, oleanolic and ursolic acids inhibit the enzymatic and biological effects induced by a PI snake venom metalloproteinase","volume":"279","author":"Preciado","year":"2018","journal-title":"Chem. Biol. Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/0041-0101(94)00138-X","article-title":"Isolation and characterization of a metalloproteinase with weak hemorrhagic activity from the venom of the snake Bothrops asper (terciopelo)","volume":"33","author":"Romero","year":"1995","journal-title":"Toxicon"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"234","DOI":"10.3389\/fonc.2015.00234","article-title":"CEACAM1-4L Promotes Anchorage-Independent Growth in Melanoma","volume":"5","author":"Loffek","year":"2015","journal-title":"Front. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1002\/cam4.1438","article-title":"Anti-tumor effects of a nonsteroidal anti-inflammatory drug zaltoprofen on chondrosarcoma via activating peroxisome proliferator-activated receptor gamma and suppressing matrix metalloproteinase-2 expression","volume":"7","author":"Higuchi","year":"2018","journal-title":"Can. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1002\/cam4.104","article-title":"Inhibition of MMP 14 potentiates the therapeutic effect of temozolomide and radiation in gliomas","volume":"2","author":"Ulasov","year":"2013","journal-title":"Can. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.nano.2011.08.019","article-title":"Gadolinium metallofullerenol nanoparticles inhibit cancer metastasis through matrix metalloproteinase inhibition: Imprisoning instead of poisoning cancer cells","volume":"8","author":"Meng","year":"2012","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Le Qu\u00e9ment, C., Lagente, V., Gu\u00e9non, I., Muzio, V., Gillon, J.Y., and Boichot, E. (2008). Anti-inflammatory properties of MMP inhibitors in experimental models of chronic obstructive pulmonary disease and lung inflammation. Matrix Metalloproteinases in Tissue Remodelling and Inflammation, Springer.","DOI":"10.1007\/978-3-7643-8585-9_4"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Aerts, J., Vandenbroucke, R., Dera, R., Balusu, S., Van Wonterghem, E., Moons, L., Libert, C., Dehaen, W., and Arckens, L. (2015). Synthesis and validation of a hydroxypyrone-based, potent, and specific matrix metalloproteinase-12 inhibitor with anti-inflammatory activity in vitro and in vivo. Mediat. Inflamm., 2015.","DOI":"10.1155\/2015\/510679"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1080\/09629350220131980","article-title":"Increments in cytokines and matrix metalloproteinases in skeletal muscle after injection of tissue-damaging toxins from the venom of the snake Bothrops asper","volume":"11","author":"Rucavado","year":"2002","journal-title":"Mediat. Inflamm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2571","DOI":"10.1016\/j.bbagen.2014.03.007","article-title":"Matrix metalloproteinases in inflammation","volume":"1840","author":"Nissinen","year":"2014","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.semcdb.2007.07.003","article-title":"Matrix metalloproteinases as modulators of inflammation","volume":"Volume 19","author":"Manicone","year":"2008","journal-title":"Seminars in Cell & Developmental Biology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3144","DOI":"10.1021\/ci300363c","article-title":"Automation of the CHARMM General Force Field (CGenFF) I: Bond perception and atom typing","volume":"52","author":"Vanommeslaeghe","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/nmeth.4067","article-title":"CHARMM36m: An improved force field for folded and intrinsically disordered proteins","volume":"14","author":"Huang","year":"2017","journal-title":"Nat. Meth."},{"key":"ref_46","first-page":"4738","article-title":"Zooming across the Free-Energy Landscape: Shaving Barriers, and Flooding Valleys","volume":"9","author":"Fu","year":"2018","journal-title":"J. Chem. Theory Comput."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"295","DOI":"10.2174\/1381612053382115","article-title":"Recent developments in the design of specific matrix metalloproteinase inhibitors aided by structural and computational studies","volume":"11","author":"Rao","year":"2005","journal-title":"Curr. Pharm. Des."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"368","DOI":"10.2174\/092986708783497300","article-title":"Role of sulfonamide group in matrix metalloproteinase inhibitors","volume":"15","author":"Cheng","year":"2008","journal-title":"Curr. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1038\/227680a0","article-title":"Cleavage of structural proteins during the assembly of the head of bacteriophage T4","volume":"227","author":"Laemmli","year":"1970","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/0041-0101(85)90380-0","article-title":"Neutralization of proteolytic and hemorrhagic activities of Costa Rican snake venoms by a polyvalent antivenom","volume":"23","author":"Rojas","year":"1985","journal-title":"Toxicon"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3155","DOI":"10.1021\/ci3003649","article-title":"Automation of the CHARMM General Force Field (CGenFF) II: Assignment of bonded parameters and partial atomic charges","volume":"52","author":"Vanommeslaeghe","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.1021\/ct300400x","article-title":"Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone \u03d5, \u03c8 and side-chain \u03c71 and \u03c72 dihedral angles","volume":"8","author":"Best","year":"2012","journal-title":"J. Chem. Theory Comput."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1002\/jcc.20945","article-title":"CHARMM-GUI: A web-based graphical user interface for CHARMM","volume":"29","author":"Jo","year":"2008","journal-title":"J. Comput. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1021\/acs.jctc.5b00935","article-title":"CHARMM-GUI input generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM\/OpenMM simulations using the CHARMM36 additive force field","volume":"12","author":"Lee","year":"2015","journal-title":"J. Chem. Theory Comput."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1002\/jcc.20289","article-title":"Scalable molecular dynamics with NAMD","volume":"26","author":"Phillips","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD\u2014Visual Molecular Dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graphics"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.1021\/ct5010406","article-title":"Long-time-step molecular dynamics through hydrogen mass repartitioning","volume":"11","author":"Hopkins","year":"2015","journal-title":"J. Chem. Theory Comput."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle mesh Ewald: An N log N method for Ewald sums in large systems","volume":"98","author":"Darden","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of Simple Potential Functions for Simulating Liquid Water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"key":"ref_60","first-page":"3345","article-title":"Using collective variables to drive molecular dynamics simulations","volume":"111","author":"Fiorin","year":"2013","journal-title":"Math. Probl. Eng."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"9169","DOI":"10.1063\/1.1410978","article-title":"Calculating Free Energies Using Average Force","volume":"115","author":"Darve","year":"2001","journal-title":"J. Chem. Phys."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1080\/08927022.2013.841909","article-title":"Achieving Ergodic Sampling Using Replica-exchange Free-energy Calculations","volume":"40","author":"Comer","year":"2014","journal-title":"Mol. Simul."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3506","DOI":"10.1021\/acs.jctc.6b00447","article-title":"Extended adaptive biasing force algorithm. An on-the-fly implementation for accurate free-energy calculations","volume":"12","author":"Fu","year":"2016","journal-title":"J. Chem. Theory Comput."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"090601","DOI":"10.1103\/PhysRevLett.96.090601","article-title":"Equilibrium free energies from nonequilibrium metadynamics","volume":"96","author":"Bussi","year":"2006","journal-title":"Phys. Rev. Lett."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"6358","DOI":"10.1073\/pnas.1303186110","article-title":"Funnel metadynamics as accurate binding free-energy method","volume":"110","author":"Limongelli","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/12\/1\/8\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:44:15Z","timestamp":1760190255000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/12\/1\/8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,20]]},"references-count":65,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["toxins12010008"],"URL":"https:\/\/doi.org\/10.3390\/toxins12010008","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,20]]}}}