{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T04:05:31Z","timestamp":1783569931649,"version":"3.55.0"},"reference-count":75,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"State of Nebraska","award":["LB595"],"award-info":[{"award-number":["LB595"]}]},{"name":"State of Nebraska","award":["LB595"],"award-info":[{"award-number":["LB595"]}]},{"name":"Creighton University School of Medicine M1 Summer Research Program"},{"name":"Kick for a Cure, Inc."}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Glioblastoma aggressively invades surrounding tissue by expressing matrix metalloproteinase-2 (MMP-2). Therefore, effective inhibition of MMP-2 is a desirable target for treatment. In some reports, the chlorotoxin (Ctx) polypeptide produced by the scorpion\n                    <jats:italic>Leiurus quinquestriatus,<\/jats:italic>\n                    interacts with human MMP-2 to inhibit tumor invasion without affecting surrounding tissue. We employed three molecular docking methodologies followed by molecular dynamics simulations to find consensus binding and calculate the binding energy of these peptide ligands to MMP-2. In addition to the Ctx itself, four C-terminal fragments were chosen to study their binding to MMP-2. The molecular docking platforms HPEPDOCK, HADDOCK, and AlphaFold2 created peptide \u2013 protein poses for each candidate binding to MMP-2. These poses underwent 500\u00a0ns molecular dynamics simulations. Peptide binding on MMP-2 and final binding energies were calculated using the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) method. Configurational entropy and root-mean square deviation analyses showed stable peptide \u2013 protein complexes. Ctx and its peptide fragments frequently bound to regions on MMP-2 other than the catalytic site. All docking methods shared consensus on large negative binding energies, indicating favorable interaction between Ctx and its analogs with MMP-2. While Ctx and its fragments bind to MMP-2, there is no consensus on which region of MMP-2 they are bound to or which peptide binds strongest. Neither Ctx nor its fragments inhibited MMP-2 enzymatic activity, however, glioblastoma cellular migration was inhibited. Interactions with the non-catalytic regions of MMP-2 suggest allosteric binding to MMP-2. Inhibition of cellular migration without inhibition of MMP-2 activity warrants further study into the possible targets of Ctx expressed in glioblastoma.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0328964","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T17:25:22Z","timestamp":1775755522000},"page":"e0328964","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Chlorotoxin does not target matrix metalloproteinase-2\u00a0in glioblastoma"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9956-2510","authenticated-orcid":true,"given":"Eli","family":"Blaney","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meron","family":"Demeke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seraphine","family":"Kamayirese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Monga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura A.","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5011-487X","authenticated-orcid":true,"given":"Charles 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Biophys Acta Rev Cancer"},{"issue":"9","key":"pone.0328964.ref003","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1177\/0271678X16655551","article-title":"Matrix metalloproteinases in the brain and blood-brain barrier: Versatile breakers and makers","volume":"36","author":"RG Rempe","year":"2016","journal-title":"J Cereb Blood Flow Metab"},{"key":"pone.0328964.ref004","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.pmbts.2017.02.005","article-title":"Biochemical and Biological Attributes of Matrix Metalloproteinases","volume":"147","author":"N Cui","year":"2017","journal-title":"Prog Mol Biol Transl Sci"},{"issue":"8","key":"pone.0328964.ref005","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1161\/01.RES.0000070112.80711.3D","article-title":"Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry","volume":"92","author":"R Visse","year":"2003","journal-title":"Circ 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Coussens","year":"2002","journal-title":"Science"},{"key":"pone.0328964.ref009","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1038\/sj.bjc.6690291","article-title":"Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas","volume":"79","author":"PA Forsyth","year":"1999","journal-title":"Br J Cancer"},{"issue":"17","key":"pone.0328964.ref010","doi-asserted-by":"crossref","first-page":"4194","DOI":"10.3390\/ijms20174194","article-title":"Conformation and domain movement analysis of human matrix metalloproteinase-2: role of associated Zn2 and Ca2 ions","volume":"20","author":"L Voit-Ostricki","year":"2019","journal-title":"Int J Mol Sci"},{"issue":"8","key":"pone.0328964.ref011","doi-asserted-by":"crossref","first-page":"3884","DOI":"10.1073\/pnas.97.8.3884","article-title":"Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype 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Ramachandran","year":"2017","journal-title":"PLoS One"},{"issue":"1","key":"pone.0328964.ref015","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1023\/A:1006421112839","article-title":"Matrix metalloproteinase 2 (MMP-2) immunoreactive protein is associated with poor grade and survival in brain neoplasms","volume":"46","author":"J J\u00e4\u00e4linoj\u00e4","year":"2000","journal-title":"J Neurooncol"},{"issue":"1","key":"pone.0328964.ref016","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1186\/s12890-020-01317-1","article-title":"Correlation between MMP2 expression in lung cancer tissues and clinical parameters: a retrospective clinical analysis","volume":"20","author":"L Han","year":"2020","journal-title":"BMC Pulm Med"},{"issue":"5","key":"pone.0328964.ref017","article-title":"Effect of synthetic matrix-metalloproteinase inhibitors on invasive capacity and proliferation of human malignant gliomas in vitro","volume":"80","author":"JC Tonn","year":"1999","journal-title":"Int J Cancer"},{"issue":"1","key":"pone.0328964.ref018","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1080\/17460441.2018.1398732","article-title":"Recent opportunities in matrix metalloproteinase inhibitor drug design for cancer","volume":"13","author":"Y Zhong","year":"2018","journal-title":"Expert Opin Drug Discov"},{"issue":"11","key":"pone.0328964.ref019","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1016\/0041-0101(91)90128-E","article-title":"Chloride channel inhibition by the venom of the scorpion Leiurus quinquestriatus","volume":"29","author":"JA DeBin","year":"1991","journal-title":"Toxicon"},{"issue":"2","key":"pone.0328964.ref020","doi-asserted-by":"crossref","DOI":"10.1152\/ajpcell.1993.264.2.C361","article-title":"Purification and characterization of chlorotoxin, a chloride channel ligand from the venom of the scorpion","volume":"264","author":"JA DeBin","year":"1993","journal-title":"Am J Physiol-Cell Physiol"},{"issue":"15","key":"pone.0328964.ref021","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.4155\/fmc.14.93","article-title":"The role of disulfide bonds in structure and activity of chlorotoxin","volume":"6","author":"PG Ojeda","year":"2014","journal-title":"Future Med Chem"},{"issue":"6","key":"pone.0328964.ref022","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.3390\/ijms20061261","article-title":"Effects of selective substitution of cysteine residues on the conformational properties of chlorotoxin explored by molecular dynamics simulations","volume":"20","author":"A Gregory","year":"2019","journal-title":"Int J Mol Sci"},{"issue":"13","key":"pone.0328964.ref023","doi-asserted-by":"crossref","first-page":"5572","DOI":"10.1523\/JNEUROSCI.23-13-05572.2003","article-title":"Expression of voltage-gated chloride channels in human glioma cells","volume":"23","author":"ML Olsen","year":"2003","journal-title":"J Neurosci"},{"issue":"21","key":"pone.0328964.ref024","first-page":"4871","article-title":"Use of chlorotoxin for targeting of primary brain tumors","volume":"58","author":"L Soroceanu","year":"1998","journal-title":"Cancer Res"},{"issue":"2","key":"pone.0328964.ref025","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1002\/glia.10083","article-title":"Chlorotoxin, a scorpion-derived peptide, specifically binds to gliomas and tumors of neuroectodermal origin","volume":"39","author":"SA Lyons","year":"2002","journal-title":"Glia"},{"issue":"4","key":"pone.0328964.ref026","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1016\/S0306-4522(97)00456-9","article-title":"Expression of voltage-activated chloride currents in acute slices of human gliomas","volume":"83","author":"N Ullrich","year":"1998","journal-title":"Neuroscience"},{"issue":"4","key":"pone.0328964.ref027","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1038\/sj.bjp.0703102","article-title":"Chlorotoxin does not inhibit volume-regulated, calcium-activated and cyclic AMP-activated chloride channels","volume":"129","author":"C Maertens","year":"2000","journal-title":"Br J Pharmacol"},{"issue":"6","key":"pone.0328964.ref028","doi-asserted-by":"crossref","first-page":"4135","DOI":"10.1074\/jbc.M205662200","article-title":"Chlorotoxin Inhibits Glioma Cell Invasion via Matrix Metalloproteinase-2","volume":"278","author":"J Deshane","year":"2003","journal-title":"J Biol Chem"},{"issue":"6","key":"pone.0328964.ref029","article-title":"Tumor-targeted Chlorotoxin-coupled Nanoparticles for Nucleic Acid Delivery to Glioblastoma Cells: A Promising System for Glioblastoma Treatment","volume":"2","author":"PM Costa","year":"2013","journal-title":"Mol Ther Nucleic Acids"},{"key":"pone.0328964.ref030","unstructured":"Maertens C. Chlorotoxin does not inhibit volume-regulated, calcium-activated and cyclic AMP-activated chloride channels."},{"issue":"22","key":"pone.0328964.ref031","doi-asserted-by":"crossref","first-page":"5908","DOI":"10.1016\/j.biomaterials.2014.03.077","article-title":"The impact of a chlorotoxin-modified liposome system on receptor MMP-2 and the receptor-associated protein ClC-3","volume":"35","author":"C Qin","year":"2014","journal-title":"Biomaterials"},{"key":"pone.0328964.ref032","unstructured":"DeBin JA. Purification and characterization of chlorotoxin, a chloride channel ligand from the venom of scorpion. 2023."},{"issue":"13","key":"pone.0328964.ref033","doi-asserted-by":"crossref","first-page":"2815","DOI":"10.1080\/07391102.2016.1231633","article-title":"In Silico prediction of the molecular basis of ClTx and AaCTx interaction with matrix metalloproteinase-2 (MMP-2) to inhibit glioma cell invasion","volume":"35","author":"H Othman","year":"2017","journal-title":"J Biomol Struct Dyn"},{"issue":"3","key":"pone.0328964.ref034","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s10989-012-9293-0","article-title":"Design and synthesis of a peptidyl-FRET substrate for tumor marker enzyme human matrix metalloprotease-2 (hMMP-2)","volume":"18","author":"M Alam","year":"2012","journal-title":"Int J Pept Res Ther"},{"issue":"9","key":"pone.0328964.ref035","doi-asserted-by":"crossref","first-page":"104998","DOI":"10.1016\/j.jbc.2023.104998","article-title":"Chlorotoxin binds to both matrix metalloproteinase 2 and neuropilin 1","volume":"299","author":"S Farkas","year":"2023","journal-title":"J Biol Chem"},{"key":"pone.0328964.ref036","author":"Cedars-Sinai Medical Center RP"},{"key":"pone.0328964.ref037","doi-asserted-by":"crossref","first-page":"100830","DOI":"10.1016\/j.conctc.2021.100830","article-title":"A first-in-human study of BLZ-100 (tozuleristide) demonstrates tolerability and safety in skin cancer patients","volume":"23","author":"M Yamada","year":"2021","journal-title":"Contemp Clin Trials Commun"},{"key":"pone.0328964.ref038","author":"Blaze Bioscience Australia Pty Ltd"},{"issue":"4","key":"pone.0328964.ref039","doi-asserted-by":"crossref","DOI":"10.1093\/neuros\/nyz125","article-title":"Phase 1 safety, pharmacokinetics, and fluorescence imaging study of tozuleristide (BLZ-100) in adults with newly diagnosed or recurrent gliomas","volume":"85","author":"CG Patil","year":"2019","journal-title":"Neurosurgery"},{"issue":"2","key":"pone.0328964.ref040","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1093\/neuros\/nyab106","article-title":"Unexpected Binding of Tozuleristide \u201cTumor Paint\u201d to Cerebral Vascular Malformations: A Potentially Novel Application of Fluorescence-Guided Surgery","volume":"89","author":"AJ Kobets","year":"2021","journal-title":"Neurosurgery"},{"key":"pone.0328964.ref041","author":"City of Hope Medical Center"},{"issue":"533","key":"pone.0328964.ref042","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aaw2672","article-title":"Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma","volume":"12","author":"D Wang","year":"2020","journal-title":"Sci Transl Med"},{"issue":"2","key":"pone.0328964.ref043","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.nec.2020.12.005","volume":"32","author":"T Tudor","year":"2021","journal-title":"Neurosurg Clin N Am"},{"key":"pone.0328964.ref044","doi-asserted-by":"crossref","first-page":"250","DOI":"10.3389\/fphar.2019.00250","article-title":"A C-Terminal Fragment of Chlorotoxin Retains Bioactivity and Inhibits Cell Migration","volume":"10","author":"M Dastpeyman","year":"2019","journal-title":"Front Pharmacol"},{"issue":"1","key":"pone.0328964.ref045","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The protein data bank","volume":"28","author":"HM Berman","year":"2000","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"pone.0328964.ref046","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1021\/bi00001a003","article-title":"NMR sequential assignments and solution structure of chlorotoxin, a small scorpion toxin that blocks chloride channels","volume":"34","author":"G Lippens","year":"1995","journal-title":"Biochemistry"},{"issue":"17","key":"pone.0328964.ref047","doi-asserted-by":"crossref","first-page":"4109","DOI":"10.1093\/bioinformatics\/btac486","article-title":"Docking cyclic peptides formed by a disulfide bond through a hierarchical strategy","volume":"38","author":"H Tao","year":"2022","journal-title":"Bioinformatics"},{"key":"pone.0328964.ref048","doi-asserted-by":"crossref","first-page":"729513","DOI":"10.3389\/fmolb.2021.729513","article-title":"Structural Biology in the Clouds: The WeNMR-EOSC Ecosystem","volume":"8","author":"RV Honorato","year":"2021","journal-title":"Front Mol Biosci"},{"issue":"7873","key":"pone.0328964.ref049","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"J Jumper","year":"2021","journal-title":"Nature"},{"key":"pone.0328964.ref050","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gky357","article-title":"HPEPDOCK: a web server for blind peptide-protein docking based on a hierarchical algorithm","volume":"46","author":"P Zhou","year":"2018","journal-title":"Nucleic Acids Res"},{"issue":"7","key":"pone.0328964.ref051","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1021\/ja026939x","article-title":"HADDOCK: A Protein\u2212Protein Docking Approach Based on Biochemical or Biophysical Information","volume":"125","author":"C Dominguez","year":"2003","journal-title":"J Am Chem Soc"},{"issue":"6","key":"pone.0328964.ref052","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/s41592-022-01488-1","article-title":"ColabFold: making protein folding accessible to all","volume":"19","author":"M Mirdita","year":"2022","journal-title":"Nat Methods"},{"issue":"13","key":"pone.0328964.ref053","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1002\/jcc.23899","article-title":"New ways to boost molecular dynamics simulations","volume":"36","author":"E Krieger","year":"2015","journal-title":"J Comput Chem"},{"key":"pone.0328964.ref054","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/978-1-4939-7366-8_4","article-title":"YASARA: A Tool to Obtain Structural Guidance in Biocatalytic Investigations","volume":"1685","author":"H Land","year":"2018","journal-title":"Methods Mol Biol"},{"issue":"16","key":"pone.0328964.ref055","doi-asserted-by":"crossref","first-page":"4023","DOI":"10.1021\/acs.jpcb.7b02320","article-title":"Building a more predictive protein force field: a systematic and reproducible route to AMBER-FB15","volume":"121","author":"LP Wang","year":"2017","journal-title":"J Phys Chem B"},{"issue":"19","key":"pone.0328964.ref056","doi-asserted-by":"crossref","first-page":"8577","DOI":"10.1063\/1.470117","article-title":"A smooth particle mesh Ewald method","volume":"103","author":"U Essmann","year":"1995","journal-title":"J Chem Phys"},{"key":"pone.0328964.ref057","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","author":"MJ Abraham","year":"2015","journal-title":"SoftwareX"},{"issue":"1","key":"pone.0328964.ref058","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":"J Huang","year":"2017","journal-title":"Nat Methods"},{"issue":"2","key":"pone.0328964.ref059","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":"WL Jorgensen","year":"1983","journal-title":"J Chem Phys"},{"issue":"1","key":"pone.0328964.ref060","doi-asserted-by":"crossref","first-page":"014101","DOI":"10.1063\/1.2408420","article-title":"Canonical sampling through velocity rescaling","volume":"126","author":"G Bussi","year":"2007","journal-title":"J Chem Phys"},{"issue":"8","key":"pone.0328964.ref061","article-title":"Molecular dynamics with coupling to an external bath","volume":"81","author":"HJC Berendsen","year":"1984","journal-title":"J Chem Phys"},{"issue":"12","key":"pone.0328964.ref062","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1002\/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H","article-title":"LINCS: A linear constraint solver for molecular simulations","volume":"18","author":"H Berk","year":"1997","journal-title":"J Comput Chem"},{"issue":"12","key":"pone.0328964.ref063","doi-asserted-by":"crossref","first-page":"7182","DOI":"10.1063\/1.328693","article-title":"Polymorphic transitions in single crystals: A new molecular dynamics method","volume":"52","author":"M Parrinello","year":"1981","journal-title":"J Appl Phys"},{"key":"pone.0328964.ref064","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1080\/08927029108022142","article-title":"Generalized verlet algorithm for efficient molecular dynamics simulations with long-range interactions","volume":"6","author":"H Grubm\u00fcller","year":"1991","journal-title":"Mol Simul"},{"issue":"10","key":"pone.0328964.ref065","doi-asserted-by":"crossref","first-page":"6281","DOI":"10.1021\/acs.jctc.1c00645","article-title":"gmx_MMPBSA: A New Tool to Perform End-State Free Energy Calculations with GROMACS","volume":"17","author":"MS Vald\u00e9s-Tresanco","year":"2021","journal-title":"J Chem Theory Comput"},{"key":"pone.0328964.ref066","article-title":"Supporting Information gmx_MMPBSA: a new tool aid to perform end-state free energy calculations with GROMACS files","author":"MS Vald\u00e9s-Tresanco","year":"2023","journal-title":"N\/A"},{"issue":"2","key":"pone.0328964.ref067","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1021\/ma50003a019","article-title":"Method for estimating the configurational entropy of macromolecules","volume":"14","author":"M Karplus","year":"1981","journal-title":"Macromolecules"},{"issue":"14","key":"pone.0328964.ref068","doi-asserted-by":"crossref","first-page":"6289","DOI":"10.1063\/1.1401821","article-title":"On the calculation of entropy from covariance matrices of the atomic fluctuations","volume":"115","author":"I Andricioaei","year":"2001","journal-title":"J Chem Phys"},{"issue":"3","key":"pone.0328964.ref069","doi-asserted-by":"crossref","first-page":"031910","DOI":"10.1103\/PhysRevE.65.031910","article-title":"Convergence of sampling in protein simulations","volume":"65","author":"B Hess","year":"2002","journal-title":"Phys Rev E"},{"key":"pone.0328964.ref070","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1002\/(SICI)1521-3773(19990115)38:1\/2<236::AID-ANIE236>3.0.CO;2-M","article-title":"Peptide folding: when simulation meets experiment","volume":"38","author":"X Daura","year":"1999","journal-title":"Angew Chem Int Ed"},{"issue":"2","key":"pone.0328964.ref071","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1021\/acsomega.3c07740","article-title":"Optimizing phosphopeptide structures that target 14-3-3\u03b5 in cutaneous squamous cell carcinoma","volume":"9","author":"S Kamayirese","year":"2024","journal-title":"ACS 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