{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T06:28:29Z","timestamp":1777616909787,"version":"3.51.4"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: One goal of metabolomics is to define and monitor the entire metabolite complement of a cell, while it is still far from reach since systematic and rapid approaches for determining the biotransformations of newly discovered metabolites are lacking. For drug development, such metabolic biotransformation of a new chemical entity (NCE) is of more interest because it may profoundly affect its bioavailability, activity and toxicity profile. The use of in silico methods to predict the site of metabolism (SOM) in phase I cytochromes P450-mediated reactions is usually a starting point of metabolic pathway studies, which may also assist in the process of drug\/lead optimization.<\/jats:p>\n               <jats:p>Results: This article reports the Cytochromes P450 (CYP450)-mediated SOM prediction for the six most important metabolic reactions by incorporating the use of machine learning and semi-empirical quantum chemical calculations. Non-local models were developed on the basis of a large dataset comprising 1858 metabolic reactions extracted from 1034 heterogeneous chemicals. For validation, the overall accuracies of all six reaction types are higher than 0.81, four of which exceed 0.90. In further receiver operating characteristic (ROC) analyses, each of the SOM model gave a significant area under curve (AUC) value over 0.86, indicating a good predicting power. An external test was made on a previously published dataset, of which 80% of the experimentally observed SOMs can be correctly identified by applying the full set of our SOM models.<\/jats:p>\n               <jats:p>Availability: The program package SOME_v1.0 (Site Of Metabolism Estimator) developed based on our models is available at http:\/\/www.dddc.ac.cn\/adme\/myzheng\/SOME_1_0.tar.gz.<\/jats:p>\n               <jats:p>Contact: \u00a0xmluo@mail.shcnc.ac.cn; hljiang@mail.shcnc.ac.cn<\/jats:p>","DOI":"10.1093\/bioinformatics\/btp140","type":"journal-article","created":{"date-parts":[[2009,3,14]],"date-time":"2009-03-14T00:49:45Z","timestamp":1236991785000},"page":"1251-1258","source":"Crossref","is-referenced-by-count":108,"title":["Site of metabolism prediction for six biotransformations mediated by cytochromes P450"],"prefix":"10.1093","volume":"25","author":[{"given":"Mingyue","family":"Zheng","sequence":"first","affiliation":[{"name":"1 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203 and 2School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaomin","family":"Luo","sequence":"additional","affiliation":[{"name":"1 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203 and 2School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiancheng","family":"Shen","sequence":"additional","affiliation":[{"name":"1 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203 and 2School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong","family":"Wang","sequence":"additional","affiliation":[{"name":"1 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203 and 2School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun","family":"Du","sequence":"additional","affiliation":[{"name":"1 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203 and 2School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiliang","family":"Zhu","sequence":"additional","affiliation":[{"name":"1 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203 and 2School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China"},{"name":"1 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203 and 2School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hualiang","family":"Jiang","sequence":"additional","affiliation":[{"name":"1 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203 and 2School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China"},{"name":"1 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203 and 2School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2009,3,13]]},"reference":[{"key":"2023013110284355400_B1","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1080\/03602530600969374","article-title":"State-of-the-art tools for computational site of metabolism predictions: comparative analysis, mechanistical insights, and future applications","volume":"39","author":"Afzelius","year":"2007","journal-title":"Drug Metab. Rev."},{"key":"2023013110284355400_B2","first-page":"1","article-title":"A case study for learning from imbalanced data sets","volume-title":"Proceedings of the 14th Biennial Conference of the Canadian Society on Computational Studies of Intelligence: Advances in Artificial Intelligence.","author":"Aijun","year":"2001"},{"key":"2023013110284355400_B3","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1093\/bioinformatics\/16.5.412","article-title":"Assessing the accuracy of prediction algorithms for classification: an overview","volume":"16","author":"Baldi","year":"2000","journal-title":"Bioinformatics"},{"key":"2023013110284355400_B4","first-page":"491","article-title":"Retrometabolic approaches for drug design and targeting","volume":"52","author":"Bodor","year":"1997","journal-title":"Pharmazie"},{"key":"2023013110284355400_B5","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1023\/A:1009715923555","article-title":"A tutorial on support vector machines for pattern recognition","volume":"2","author":"Burges","year":"1998","journal-title":"Data Min. Know. Disc."},{"key":"2023013110284355400_B6","author":"Chang","year":"2001","journal-title":"LIBSVM : a library for support vector machines."},{"key":"2023013110284355400_B7","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1021\/tx00041a002","article-title":"Molecular orbital-based quantitative structure-activity relationship for the cytochrome P450-catalyzed 4-hydroxylation of halogenated anilines","volume":"7","author":"Cnubben","year":"1994","journal-title":"Chem. Res. Toxicol."},{"key":"2023013110284355400_B8","doi-asserted-by":"crossref","first-page":"6970","DOI":"10.1021\/jm050529c","article-title":"MetaSite: understanding metabolism in human cytochromes from the perspective of the chemist","volume":"48","author":"Cruciani","year":"2005","journal-title":"J. Med. Chem."},{"key":"2023013110284355400_B9","volume-title":"Theory and Practice of MO Calculations on Organic Molecules.","author":"Csizmadia","year":"1976"},{"key":"2023013110284355400_B10","doi-asserted-by":"crossref","first-page":"2725","DOI":"10.1021\/jm040180d","article-title":"Cytochrome p450 in silico: an integrative modeling approach","volume":"48","author":"de Graaf","year":"2005","journal-title":"J. Med. Chem."},{"key":"2023013110284355400_B11","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.1021\/jm0508538","article-title":"Catalytic site prediction and virtual screening of cytochrome P450 2D6 substrates by consideration of water and rescoring in automated docking","volume":"49","author":"de Graaf","year":"2006","journal-title":"J. Med. Chem."},{"key":"2023013110284355400_B12","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.1021\/cr0307143","article-title":"Structure and chemistry of cytochrome P450","volume":"105","author":"Denisov","year":"2005","journal-title":"Chem. Rev."},{"key":"2023013110284355400_B13","article-title":"ROC graphs: notes and practical considerations for researchers","volume-title":"Technical Report HPL-2003-4, Mach. Learn.","author":"Fawcett","year":"2004"},{"key":"2023013110284355400_B14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BFb0051113","article-title":"Theory of orientation and stereoselection","volume-title":"Orientation and Stereoselection.","author":"Fukui","year":"1970"},{"key":"2023013110284355400_B15","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1063\/1.1743986","article-title":"MO-theoretical approach to the mechanism of charge transfer in the process of aromatic substitutions","volume":"27","author":"Fukui","year":"1957","journal-title":"J. Chem. Phys."},{"key":"2023013110284355400_B16","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S1359-6446(05)03681-0","article-title":"Role of pharmacologically active metabolites in drug discovery and development","volume":"11","author":"Fura","year":"2006","journal-title":"Drug Discov. Today"},{"key":"2023013110284355400_B17","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s10822-006-9097-4","article-title":"Modeling chemical reactions for drug design","volume":"21","author":"Gasteiger","year":"2007","journal-title":"J. Comput. Aided Mol. Des."},{"key":"2023013110284355400_B18","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/0898-5529(90)90156-3","article-title":"Automatic generation of 3d-atomic coordinates for organic molecules","volume":"3","author":"Gasteiger","year":"1990","journal-title":"Tetrahedron Comput. Methods"},{"key":"2023013110284355400_B19","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1126\/science.157.3796.1524","article-title":"Hydroxylation-induced migration: the NIH shift. Recent experiments reveal an unexpected and general result of enzymatic hydroxylation of aromatic compounds","volume":"157","author":"Guroff","year":"1967","journal-title":"Science"},{"key":"2023013110284355400_B20","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1148\/radiology.143.1.7063747","article-title":"The meaning and use of the area under a receiver operating characteristic (ROC) curve","volume":"143","author":"Hanley","year":"1982","journal-title":"Radiology"},{"key":"2023013110284355400_B21","article-title":"Daylight Theory Manual","volume-title":"Daylight Chemical Information Systems, Inc.","author":"James","year":"2004"},{"key":"2023013110284355400_B22","volume-title":"CODESSA Reference Manual, Version 2.0.","author":"Katritzky","year":"1995"},{"key":"2023013110284355400_B23","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/3-540-57868-4_57","article-title":"Estimating attributes: analysis and extensions of RELIEF","volume-title":"Machine Learning: ECML-94.","author":"Kononenko","year":"1994"},{"key":"2023013110284355400_B24","doi-asserted-by":"crossref","first-page":"3631","DOI":"10.1021\/jm030102a","article-title":"Modeling of human cytochrome P450-mediated drug metabolism using unsupervised machine learning approach","volume":"46","author":"Korolev","year":"2003","journal-title":"J. Med. Chem."},{"key":"2023013110284355400_B25","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/S0169-409X(02)00011-X","article-title":"Computer systems for the prediction of xenobiotic metabolism","volume":"54","author":"Langowski","year":"2002","journal-title":"Adv. Drug Deliver. Rev."},{"key":"2023013110284355400_B26","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1081\/DMR-120001391","article-title":"Structure-activity relationship for human cytochrome P450 substrates and inhibitors","volume":"34","author":"Lewis","year":"2002","journal-title":"Drug Metab. Rev."},{"key":"2023013110284355400_B27","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1021\/ci049875d","article-title":"A comparative study on feature selection methods for drug discovery","volume":"44","author":"Liu","year":"2004","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"2023013110284355400_B28","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1145\/1150402.1150531","article-title":"YALE: Rapid Prototyping for Complex Data Mining Tasks","volume-title":"Proceedings of the 12th ACM SIGKDD International Conference on Knowledge Discovery and Data Mining.","author":"Mierswa","year":"2006"},{"key":"2023013110284355400_B29","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1063\/1.1740588","article-title":"Electronic population analysis on LCAO-MO molecular wave functions I","volume":"23","author":"Mulliken","year":"1955","journal-title":"J. Chem. Phys."},{"key":"2023013110284355400_B30","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1002\/qsar.19930120306","article-title":"QSAR of fungicidal D3-1,2,4-thiadiazolines. Reactivity-activity correlation of SH-inhibitors","volume":"12","author":"Nakayama","year":"1993","journal-title":"Quant. Struct. Act. Relat."},{"key":"2023013110284355400_B31","article-title":"Support Vector Machines: Training and Applications","volume-title":"Technical Report: AIM-1602.","author":"Osuna","year":"1997"},{"key":"2023013110284355400_B32","first-page":"61","article-title":"Probabilistic outputs for support vector machines and comparison to regularized likelihood methods","volume-title":"Advance in Large Margin Classifiers.","author":"Platt","year":"1999"},{"key":"2023013110284355400_B33","volume-title":"C4.5: Programs for Machine Learning.","author":"Quinlan","year":"1993"},{"key":"2023013110284355400_B34","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1385\/MB:20:2:153","article-title":"Screening with tumor markers: critical issues","volume":"20","author":"Roulston","year":"2002","journal-title":"Mol. Biotechnol."},{"key":"2023013110284355400_B35","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1093\/bioinformatics\/btm344","article-title":"A review of feature selection techniques in bioinformatics","volume":"23","author":"Saeys","year":"2007","journal-title":"Bioinformatics"},{"key":"2023013110284355400_B36","first-page":"301","article-title":"AB initio molecular orbital calculations of bond index and valency","volume-title":"Advances in Quantum Chemistry.","author":"Sannigrahi","year":"1992"},{"key":"2023013110284355400_B37","doi-asserted-by":"crossref","first-page":"3173","DOI":"10.1021\/jm0613471","article-title":"Empirical regioselectivity models for human cytochromes P450 3A4, 2D6, and 2C9","volume":"50","author":"Sheridan","year":"2007","journal-title":"J. Med. Chem."},{"key":"2023013110284355400_B38","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1021\/jm020400s","article-title":"A model for predicting likely sites of CYP3A4-mediated metabolism on drug-like molecules","volume":"46","author":"Singh","year":"2003","journal-title":"J. Med. Chem."},{"key":"2023013110284355400_B39","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1002\/qua.560160306","article-title":"Molecular structure-biological activity relationships on the basis of quantum-chemical calculations","volume":"16","author":"Sklenar","year":"1979","journal-title":"International Journal of Quantum Chemistry"},{"key":"2023013110284355400_B40","doi-asserted-by":"crossref","first-page":"5311","DOI":"10.1021\/jm0495529","article-title":"Rapid prediction of chemical metabolism by human UDP-glucuronosyltransferase isoforms using quantum chemical descriptors derived with the electronegativity equalization method","volume":"47","author":"Sorich","year":"2004","journal-title":"J. Med. Chem."},{"key":"2023013110284355400_B41","volume":"13","author":"Stewart","year":"1994","journal-title":"MOPAC: a general molecular orbital package (Public Domain). QCPE program 445; Version 7.0"},{"key":"2023013110284355400_B42","volume-title":"Chemical Pattern Recognition.","author":"Strouf","year":"1986"},{"key":"2023013110284355400_B43","volume-title":"The Nature of Statistical Learning Theory (Information Science and Statistics).","author":"Vapnik","year":"1999"},{"key":"2023013110284355400_B44","first-page":"57","article-title":"Metabolite identification in drug discovery","volume":"6","author":"Watt","year":"2003","journal-title":"Curr. Opin. Drug Discov. Dev."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/25\/10\/1251\/48989787\/bioinformatics_25_10_1251.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/25\/10\/1251\/48989787\/bioinformatics_25_10_1251.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T20:37:24Z","timestamp":1675197444000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/25\/10\/1251\/269831"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,3,13]]},"references-count":44,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2009,5,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btp140","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2009,5,15]]},"published":{"date-parts":[[2009,3,13]]}}}