{"id":"https://openalex.org/W4376131689","doi":"https://doi.org/10.1021/acs.jcim.3c00061","title":"MD-Based Assessment of Covalent Inhibitors in Noncovalent Association Complexes: Learning from Cathepsin K as a Test Case","display_name":"MD-Based Assessment of Covalent Inhibitors in Noncovalent Association Complexes: Learning from Cathepsin K as a Test Case","publication_year":2023,"publication_date":"2023-05-11","ids":{"openalex":"https://openalex.org/W4376131689","doi":"https://doi.org/10.1021/acs.jcim.3c00061","pmid":"https://pubmed.ncbi.nlm.nih.gov/37165835"},"language":"en","primary_location":{"id":"doi:10.1021/acs.jcim.3c00061","is_oa":false,"landing_page_url":"https://doi.org/10.1021/acs.jcim.3c00061","pdf_url":null,"source":{"id":"https://openalex.org/S167262187","display_name":"Journal of Chemical Information and Modeling","issn_l":"1549-9596","issn":["1549-9596","1549-960X"],"is_oa":false,"is_in_doaj":false,"is_core":true,"host_organization":"https://openalex.org/P4310320006","host_organization_name":"American Chemical Society","host_organization_lineage":["https://openalex.org/P4310320006"],"host_organization_lineage_names":["American Chemical Society"],"type":"journal"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Journal of Chemical Information and Modeling","raw_type":"journal-article"},"type":"article","indexed_in":["crossref","pubmed"],"open_access":{"is_oa":false,"oa_status":"closed","oa_url":null,"any_repository_has_fulltext":false},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5013427306","display_name":"Erik Endres","orcid":"https://orcid.org/0000-0001-8617-587X"},"institutions":[{"id":"https://openalex.org/I25974101","display_name":"University of W\u00fcrzburg","ror":"https://ror.org/00fbnyb24","country_code":"DE","type":"education","lineage":["https://openalex.org/I25974101"]}],"countries":["DE"],"is_corresponding":false,"raw_author_name":"Erik Endres","raw_affiliation_strings":["Pharmazeutische und Medizinische Chemie, Institut f\u00fcr Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universit\u00e4t W\u00fcrzburg, Am Hubland, 97074 W\u00fcrzburg, Germany"],"raw_orcid":"https://orcid.org/0000-0001-8617-587X","affiliations":[{"raw_affiliation_string":"Pharmazeutische und Medizinische Chemie, Institut f\u00fcr Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universit\u00e4t W\u00fcrzburg, Am Hubland, 97074 W\u00fcrzburg, Germany","institution_ids":["https://openalex.org/I25974101"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5063426329","display_name":"Natalia Yuan Chen","orcid":"https://orcid.org/0000-0001-5152-4670"},"institutions":[{"id":"https://openalex.org/I25974101","display_name":"University of W\u00fcrzburg","ror":"https://ror.org/00fbnyb24","country_code":"DE","type":"education","lineage":["https://openalex.org/I25974101"]}],"countries":["DE"],"is_corresponding":false,"raw_author_name":"Natalia Yuan Chen","raw_affiliation_strings":["Pharmazeutische und Medizinische Chemie, Institut f\u00fcr Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universit\u00e4t W\u00fcrzburg, Am Hubland, 97074 W\u00fcrzburg, Germany"],"raw_orcid":"https://orcid.org/0000-0001-5152-4670","affiliations":[{"raw_affiliation_string":"Pharmazeutische und Medizinische Chemie, Institut f\u00fcr Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universit\u00e4t W\u00fcrzburg, Am Hubland, 97074 W\u00fcrzburg, Germany","institution_ids":["https://openalex.org/I25974101"]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5042202366","display_name":"Christoph Sotriffer","orcid":"https://orcid.org/0000-0003-4713-4068"},"institutions":[{"id":"https://openalex.org/I25974101","display_name":"University of W\u00fcrzburg","ror":"https://ror.org/00fbnyb24","country_code":"DE","type":"education","lineage":["https://openalex.org/I25974101"]}],"countries":["DE"],"is_corresponding":true,"raw_author_name":"Christoph Sotriffer","raw_affiliation_strings":["Pharmazeutische und Medizinische Chemie, Institut f\u00fcr Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universit\u00e4t W\u00fcrzburg, Am Hubland, 97074 W\u00fcrzburg, Germany"],"raw_orcid":"https://orcid.org/0000-0003-4713-4068","affiliations":[{"raw_affiliation_string":"Pharmazeutische und Medizinische Chemie, Institut f\u00fcr Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universit\u00e4t W\u00fcrzburg, Am Hubland, 97074 W\u00fcrzburg, Germany","institution_ids":["https://openalex.org/I25974101"]}]}],"institutions":[],"countries_distinct_count":1,"institutions_distinct_count":3,"corresponding_author_ids":["https://openalex.org/A5042202366"],"corresponding_institution_ids":["https://openalex.org/I25974101"],"apc_list":null,"apc_paid":null,"fwci":1.5518,"has_fulltext":false,"cited_by_count":8,"citation_normalized_percentile":{"value":0.85183218,"is_in_top_1_percent":false,"is_in_top_10_percent":false},"cited_by_percentile_year":{"min":90,"max":99},"biblio":{"volume":"63","issue":"10","first_page":"3186","last_page":"3197"},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T10211","display_name":"Computational Drug Discovery Methods","score":0.9988999962806702,"subfield":{"id":"https://openalex.org/subfields/1703","display_name":"Computational Theory and Mathematics"},"field":{"id":"https://openalex.org/fields/17","display_name":"Computer Science"},"domain":{"id":"https://openalex.org/domains/3","display_name":"Physical Sciences"}},"topics":[{"id":"https://openalex.org/T10211","display_name":"Computational Drug Discovery Methods","score":0.9988999962806702,"subfield":{"id":"https://openalex.org/subfields/1703","display_name":"Computational Theory and Mathematics"},"field":{"id":"https://openalex.org/fields/17","display_name":"Computer Science"},"domain":{"id":"https://openalex.org/domains/3","display_name":"Physical Sciences"}},{"id":"https://openalex.org/T11162","display_name":"Enzyme Structure and Function","score":0.998199999332428,"subfield":{"id":"https://openalex.org/subfields/2505","display_name":"Materials Chemistry"},"field":{"id":"https://openalex.org/fields/25","display_name":"Materials Science"},"domain":{"id":"https://openalex.org/domains/3","display_name":"Physical Sciences"}},{"id":"https://openalex.org/T10044","display_name":"Protein Structure and Dynamics","score":0.9969000220298767,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/covalent-bond","display_name":"Covalent bond","score":0.8103821873664856},{"id":"https://openalex.org/keywords/non-covalent-interactions","display_name":"Non-covalent interactions","score":0.7438209652900696},{"id":"https://openalex.org/keywords/chemistry","display_name":"Chemistry","score":0.6932977437973022},{"id":"https://openalex.org/keywords/molecular-dynamics","display_name":"Molecular dynamics","score":0.49404528737068176},{"id":"https://openalex.org/keywords/solvation","display_name":"Solvation","score":0.49158892035484314},{"id":"https://openalex.org/keywords/protonation","display_name":"Protonation","score":0.46379074454307556},{"id":"https://openalex.org/keywords/computational-chemistry","display_name":"Computational chemistry","score":0.3766685724258423},{"id":"https://openalex.org/keywords/stereochemistry","display_name":"Stereochemistry","score":0.33458882570266724},{"id":"https://openalex.org/keywords/molecule","display_name":"Molecule","score":0.19130125641822815},{"id":"https://openalex.org/keywords/hydrogen-bond","display_name":"Hydrogen bond","score":0.1848907470703125},{"id":"https://openalex.org/keywords/organic-chemistry","display_name":"Organic chemistry","score":0.09714105725288391}],"concepts":[{"id":"https://openalex.org/C180577832","wikidata":"https://www.wikidata.org/wiki/Q127920","display_name":"Covalent bond","level":2,"score":0.8103821873664856},{"id":"https://openalex.org/C137277065","wikidata":"https://www.wikidata.org/wiki/Q2915446","display_name":"Non-covalent interactions","level":4,"score":0.7438209652900696},{"id":"https://openalex.org/C185592680","wikidata":"https://www.wikidata.org/wiki/Q2329","display_name":"Chemistry","level":0,"score":0.6932977437973022},{"id":"https://openalex.org/C59593255","wikidata":"https://www.wikidata.org/wiki/Q901663","display_name":"Molecular dynamics","level":2,"score":0.49404528737068176},{"id":"https://openalex.org/C148093993","wikidata":"https://www.wikidata.org/wiki/Q739398","display_name":"Solvation","level":3,"score":0.49158892035484314},{"id":"https://openalex.org/C30095370","wikidata":"https://www.wikidata.org/wiki/Q899488","display_name":"Protonation","level":3,"score":0.46379074454307556},{"id":"https://openalex.org/C147597530","wikidata":"https://www.wikidata.org/wiki/Q369472","display_name":"Computational chemistry","level":1,"score":0.3766685724258423},{"id":"https://openalex.org/C71240020","wikidata":"https://www.wikidata.org/wiki/Q186011","display_name":"Stereochemistry","level":1,"score":0.33458882570266724},{"id":"https://openalex.org/C32909587","wikidata":"https://www.wikidata.org/wiki/Q11369","display_name":"Molecule","level":2,"score":0.19130125641822815},{"id":"https://openalex.org/C112887158","wikidata":"https://www.wikidata.org/wiki/Q169324","display_name":"Hydrogen bond","level":3,"score":0.1848907470703125},{"id":"https://openalex.org/C178790620","wikidata":"https://www.wikidata.org/wiki/Q11351","display_name":"Organic chemistry","level":1,"score":0.09714105725288391},{"id":"https://openalex.org/C145148216","wikidata":"https://www.wikidata.org/wiki/Q36496","display_name":"Ion","level":2,"score":0.0}],"mesh":[{"descriptor_ui":"D002154","descriptor_name":"Calpain","qualifier_ui":"Q000737","qualifier_name":"chemistry","is_major_topic":false},{"descriptor_ui":"D002154","descriptor_name":"Calpain","qualifier_ui":"Q000737","qualifier_name":"chemistry","is_major_topic":false},{"descriptor_ui":"D002154","descriptor_name":"Calpain","qualifier_ui":"Q000737","qualifier_name":"chemistry","is_major_topic":false},{"descriptor_ui":"D020134","descriptor_name":"Catalytic Domain","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D020134","descriptor_name":"Catalytic Domain","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D020134","descriptor_name":"Catalytic Domain","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D056004","descriptor_name":"Molecular Dynamics Simulation","qualifier_ui":null,"qualifier_name":null,"is_major_topic":true},{"descriptor_ui":"D056004","descriptor_name":"Molecular Dynamics Simulation","qualifier_ui":null,"qualifier_name":null,"is_major_topic":true},{"descriptor_ui":"D056004","descriptor_name":"Molecular Dynamics Simulation","qualifier_ui":null,"qualifier_name":null,"is_major_topic":true},{"descriptor_ui":"D056657","descriptor_name":"Cathepsin K","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D056657","descriptor_name":"Cathepsin K","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D056657","descriptor_name":"Cathepsin K","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D057056","descriptor_name":"Cysteine Proteases","qualifier_ui":null,"qualifier_name":null,"is_major_topic":true},{"descriptor_ui":"D057056","descriptor_name":"Cysteine Proteases","qualifier_ui":null,"qualifier_name":null,"is_major_topic":true},{"descriptor_ui":"D057056","descriptor_name":"Cysteine Proteases","qualifier_ui":null,"qualifier_name":null,"is_major_topic":true}],"locations_count":2,"locations":[{"id":"doi:10.1021/acs.jcim.3c00061","is_oa":false,"landing_page_url":"https://doi.org/10.1021/acs.jcim.3c00061","pdf_url":null,"source":{"id":"https://openalex.org/S167262187","display_name":"Journal of Chemical Information and Modeling","issn_l":"1549-9596","issn":["1549-9596","1549-960X"],"is_oa":false,"is_in_doaj":false,"is_core":true,"host_organization":"https://openalex.org/P4310320006","host_organization_name":"American Chemical Society","host_organization_lineage":["https://openalex.org/P4310320006"],"host_organization_lineage_names":["American Chemical Society"],"type":"journal"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Journal of Chemical Information and Modeling","raw_type":"journal-article"},{"id":"pmid:37165835","is_oa":false,"landing_page_url":"https://pubmed.ncbi.nlm.nih.gov/37165835","pdf_url":null,"source":{"id":"https://openalex.org/S4306525036","display_name":"PubMed","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"host_organization":"https://openalex.org/I1299303238","host_organization_name":"National Institutes of Health","host_organization_lineage":["https://openalex.org/I1299303238"],"host_organization_lineage_names":[],"type":"repository"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Journal of chemical information and modeling","raw_type":null}],"best_oa_location":null,"sustainable_development_goals":[{"score":0.5,"id":"https://metadata.un.org/sdg/6","display_name":"Clean water and sanitation"}],"awards":[],"funders":[{"id":"https://openalex.org/F4320320875","display_name":"Deutscher Akademischer Austauschdienst","ror":"https://ror.org/039djdh30"}],"has_content":{"grobid_xml":false,"pdf":false},"content_urls":null,"referenced_works_count":50,"referenced_works":["https://openalex.org/W1968451199","https://openalex.org/W1975430993","https://openalex.org/W1987484678","https://openalex.org/W1992474119","https://openalex.org/W1995770177","https://openalex.org/W1998568556","https://openalex.org/W2010654750","https://openalex.org/W2011580716","https://openalex.org/W2018998879","https://openalex.org/W2022558488","https://openalex.org/W2025714344","https://openalex.org/W2026224020","https://openalex.org/W2029087609","https://openalex.org/W2046791391","https://openalex.org/W2052030759","https://openalex.org/W2067174909","https://openalex.org/W2078146467","https://openalex.org/W2084514212","https://openalex.org/W2090299301","https://openalex.org/W2096360825","https://openalex.org/W2100561975","https://openalex.org/W2107086756","https://openalex.org/W2124507977","https://openalex.org/W2130479394","https://openalex.org/W2147421370","https://openalex.org/W2147993766","https://openalex.org/W2154034955","https://openalex.org/W2164270482","https://openalex.org/W2264285591","https://openalex.org/W2295116138","https://openalex.org/W2320259688","https://openalex.org/W2332712348","https://openalex.org/W2334184216","https://openalex.org/W2336270984","https://openalex.org/W2404280981","https://openalex.org/W2524977260","https://openalex.org/W2556724632","https://openalex.org/W2563212713","https://openalex.org/W2796108867","https://openalex.org/W2808301808","https://openalex.org/W2809408016","https://openalex.org/W2904506792","https://openalex.org/W2906852657","https://openalex.org/W2914871918","https://openalex.org/W2954886265","https://openalex.org/W2973922700","https://openalex.org/W3037926269","https://openalex.org/W4224242728","https://openalex.org/W4239132621","https://openalex.org/W4293084539"],"related_works":["https://openalex.org/W2754007442","https://openalex.org/W4327759255","https://openalex.org/W2033589463","https://openalex.org/W2099826583","https://openalex.org/W1413480421","https://openalex.org/W2008081429","https://openalex.org/W2022579763","https://openalex.org/W2092434229","https://openalex.org/W2168264147","https://openalex.org/W4282824043"],"abstract_inverted_index":{"A":[0],"sufficiently":[1],"stable":[2],"noncovalent":[3,100,179,220],"association":[4],"complex":[5],"between":[6,110,137],"a":[7,17,23,44,62,67,78,120,135,241],"covalent":[8,24,86,128,222,265],"inhibitor":[9],"and":[10,97,113,139,153,171,182],"its":[11],"protein":[12],"target":[13],"is":[14,37],"regarded":[15],"as":[16,119,262],"prerequisite":[18],"for":[19,127,240],"the":[20,41,98,111,125,144,147,168,172,178,183,186,189,197,200,216,226,248,252],"formation":[21],"of":[22,43,75,82,146,151,167,185,199,229,243,251,264],"complex.":[25],"As":[26],"this":[27,48],"transient":[28],"form":[29],"can":[30],"hardly":[31],"be":[32,56,158,256],"assessed":[33],"experimentally,":[34],"computational":[35],"modeling":[36],"required":[38],"to":[39,93,104,123,143,157,188,205,214,221,236,255,258],"probe":[40],"suitability":[42,126],"given":[45],"ligand":[46],"at":[47],"particular":[49],"stage.":[50],"To":[51],"investigate":[52],"which":[53],"criteria":[54],"should":[55],"fulfilled":[57],"by":[58],"suitable":[59],"candidates":[60],"in":[61,88,196,208,225],"molecular":[63],"dynamics":[64],"(MD)":[65],"assessment,":[66],"systematic":[68],"study":[69,253],"was":[70,117,155],"conducted":[71,239],"with":[72],"20":[73],"complexes":[74,90,101,223],"cathepsin":[76,245],"K,":[77],"papain-like":[79],"cysteine":[80,260],"protease":[81],"pharmaceutical":[83],"relevance.":[84],"The":[85,107,164],"inhibitors":[87],"these":[89],"were":[91,102,202],"converted":[92],"their":[94],"pre-reaction":[95],"states,":[96],"resulting":[99,173],"subjected":[103],"MD":[105],"simulations.":[106],"critical":[108],"distance":[109,136,184],"electrophilic":[112],"nucleophilic":[114],"reaction":[115],"partners":[116],"monitored":[118],"potential":[121],"parameter":[122],"assess":[124],"bond":[129],"formation.":[130],"Across":[131],"various":[132],"warhead":[133,187,201],"types,":[134],"3.6":[138],"4.0":[140],"\u00c5,":[141],"comparable":[142],"sum":[145],"generalized":[148],"Born":[149],"radii":[150],"carbon":[152],"sulfur,":[154],"found":[156],"stably":[159],"maintained":[160],"under":[161],"appropriate":[162],"conditions.":[163],"protonation":[165],"state":[166],"catalytic":[169],"dyad":[170],"solvation":[174],"pattern":[175],"dramatically":[176],"affected":[177],"binding":[180],"mode":[181],"active":[190],"site.":[191],"For":[192],"several":[193],"complexes,":[194,247],"fluctuations":[195],"orientation":[198],"observed":[203,224],"due":[204],"torsional":[206],"rotations":[207],"adjacent":[209],"bonds.":[210],"This":[211],"observation":[212],"helped":[213],"explain":[215],"gradual":[217],"transitions":[218],"from":[219],"crystal":[227],"structures":[228],"three":[230],"closely":[231],"related":[232,259],"nitrile-based":[233],"inhibitors.":[234,266],"According":[235],"comparative":[237],"simulations":[238],"set":[242],"13":[244],"S":[246],"overall":[249],"findings":[250],"appear":[254],"transferable":[257],"proteases":[261],"targets":[263]},"counts_by_year":[{"year":2025,"cited_by_count":7},{"year":2024,"cited_by_count":1}],"updated_date":"2026-03-27T05:58:40.876381","created_date":"2025-10-10T00:00:00"}