{"corpus_id":9967492,"paper_sha":"f51a6d51b55c6500871e366234702d20606be442","doi":"10.1038/srep13471","arxiv_id":null,"pmid":null,"pmcid":"4549706","mag_id":2469922213,"dblp_id":null,"acl_id":null,"title":"Rational Design of Highly Potent and Slow-Binding Cytochrome bc1 Inhibitor as Fungicide by Computational Substitution Optimization","year":2015,"publication_date":"2015-08-26","venue":"Scientific Reports","journal":{"name":"Scientific Reports","pages":null,"volume":"5"},"journal_issn":null,"journal_title":null,"publication_types":[],"pubmed_pub_types":null,"s2_fields_of_study":["Biology","Medicine","Chemistry"],"reference_count":36,"citation_count":23,"influential_citation_count":0,"is_open_access":true,"arxiv_categories":null,"arxiv_license":null,"arxiv_journal_ref":null,"mesh_headings":null,"chemicals":null,"comments_corrections":null,"source_flags":1,"s2_open_access_pdf_url":"https://www.nature.com/articles/srep13471.pdf","s2_open_access_landing_url":"https://www.semanticscholar.org/paper/f51a6d51b55c6500871e366234702d20606be442","s2_open_access_license":"CCBY","s2_open_access_status":"GOLD","pmc_open_access_pdf_url":null,"pmc_open_access_landing_url":null,"pmc_open_access_license":null,"pmc_open_access_status":null,"unpaywall_open_access_pdf_url":null,"unpaywall_open_access_landing_url":null,"unpaywall_open_access_license":null,"unpaywall_open_access_status":null,"abstract":"Hit to lead (H2L) optimization is a key step for drug and agrochemical discovery. A critical challenge for H2L optimization is the low efficiency due to the lack of predictive method with high accuracy. We described a new computational method called Computational Substitution Optimization (CSO) that has allowed us to rapidly identify compounds with cytochrome bc1 complex inhibitory activity in the nanomolar and subnanomolar range. The comprehensively optimized candidate has proved to be a slow binding inhibitor of bc1 complex, ~73-fold more potent (Ki = 4.1 nM) than the best commercial fungicide azoxystrobin (AZ; Ki = 297.6 nM) and shows excellent in vivo fungicidal activity against downy mildew and powdery mildew disease. The excellent correlation between experimental and calculated binding free-energy shifts together with further crystallographic analysis confirmed the prediction accuracy of CSO method. To the best of our knowledge, CSO is a new computational approach to substitution-scanning mutagenesis of ligand and could be used as a general strategy of H2L optimisation in drug and agrochemical design.","claims":[{"public_id":"cl_78a26debcb7e8fa3910879475f82a63f","status":"active","text":"Computational Substitution Optimization rapidly identified compounds with cytochrome bc1 complex inhibitory activity in the nanomolar and subnanomolar range.","confidence":0.98,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_78a26debcb7e8fa3910879475f82a63f"},{"public_id":"cl_921b95738f956312bcf0080195b30c28","status":"active","text":"Experimental and calculated binding free-energy shifts correlate closely, and crystallographic analysis supports the prediction accuracy of the Computational Substitution Optimization method.","confidence":0.92,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_921b95738f956312bcf0080195b30c28"},{"public_id":"cl_c65dcbc8cbfc55f542f30a294147fc43","status":"active","text":"The comprehensively optimized candidate is a slow-binding inhibitor of the cytochrome bc1 complex and is about 73-fold more potent than azoxystrobin, with Ki = 4.1 nM versus 297.6 nM.","confidence":0.99,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_c65dcbc8cbfc55f542f30a294147fc43"},{"public_id":"cl_fa64ba5c3a06c8f9625fa4854c8a12ea","status":"active","text":"The optimized candidate shows excellent in vivo fungicidal activity against downy mildew and powdery mildew disease.","confidence":0.96,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_fa64ba5c3a06c8f9625fa4854c8a12ea"}],"concepts":[{"public_id":"co_235a90bb7cb781c75879a97876762c97","status":"active","name":"crystallographic analysis","description":"Structure-based analysis using crystallographic data to examine ligand-target interactions.","types":["analysis method"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_235a90bb7cb781c75879a97876762c97"},{"public_id":"co_3ee7ec8f4279b5d5643d6f42dbb92493","status":"active","name":"Computational Substitution Optimization","description":"A computational method for optimizing ligand substitutions during hit-to-lead 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