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In this study, we applied a structure\u2010based computational approach to predict mutants of the HIV\u20101 protease resistant to the seven FDA approved drugs. We analyzed the energetic pattern of the protease\u2010drug interaction by calculating the molecular interaction energy components (MIECs) between the drug and the protease residues. Support vector machines (SVMs) were trained on MIECs to classify protease mutants into resistant and nonresistant categories. The high prediction accuracies for the test sets of cross\u2010validations suggested that the MIECs successfully characterized the interaction interface between drugs and the HIV\u20101 protease. We conducted a proof\u2010of\u2010concept study on a newly approved drug, darunavir (TMC114), on which no drug resistance data were available in the public domain. Compared with amprenavir, our analysis suggested that darunavir might be more potent to combat drug resistance. To quantitatively estimate binding affinities of drugs and study the contributions of protease residues to causing resistance, linear regression models were trained on MIECs using partial least squares (PLS). The MIEC\u2010PLS models also achieved satisfactory prediction accuracy. Analysis of the fitting coefficients of MIECs in the regression model revealed the important resistance mutations and shed light into understanding the mechanisms of these mutations to cause resistance. Our study demonstrated the advantages of characterizing the protease\u2010drug interaction using MIECs. We believe that MIEC\u2010SVM and MIEC\u2010PLS can help design new agents or combination of therapeutic regimens to counter HIV\u20101 protease resistant strains. Proteins 2009. \u00a9 2008 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/prot.22192","type":"journal-article","created":{"date-parts":[[2008,8,14]],"date-time":"2008-08-14T18:17:43Z","timestamp":1218737863000},"page":"837-846","source":"Crossref","is-referenced-by-count":80,"title":["Predicting drug resistance of the HIV\u20101 protease using molecular interaction energy components"],"prefix":"10.1002","volume":"74","author":[{"given":"Tingjun","family":"Hou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2008,8,14]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.280.5371.1871"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.qai.0000147526.64863.53"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkh021"},{"key":"e_1_2_6_5_2","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1177\/135965350400900307","article-title":"Simple linear model provides highly accurate genotypic predictions of HIV\u20101 drug resistance","volume":"9","author":"Wang K","year":"2004","journal-title":"Antivir Ther"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0607274103"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.112177799"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bti654"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btm353"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2006.05.003"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1086\/377453"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00894-004-0205-x"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1093-3263(02)00149-3"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1110\/ps.0301103"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm960541s"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.251265598"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/12.6.469"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.21808"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm0609162"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1093-3263(01)00091-2"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1359-6446(05)03377-5"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2007.12.054"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg100"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00115a028"},{"key":"e_1_2_6_25_2","doi-asserted-by":"crossref","first-page":"26344","DOI":"10.1016\/S0021-9258(18)47199-2","article-title":"Crystal\u2010structure at 1.9\u2010angstrom resolution of human\u2010immunodeficiency\u2010virus (HIV)\u2010Ii protease complexed with l\u2010735,524, an orally bioavailable inhibitor of the HIV proteases","volume":"269","author":"Chen ZG","year":"1994","journal-title":"J Biol Chem"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.7.2484"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm9704098"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00108a056"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0896(02)00051-2"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02706-06"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444904004743"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20290"},{"key":"e_1_2_6_33_2","volume-title":"Gaussian 98","author":"Frisch MJ","year":"1998"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmgm.2005.12.005"},{"key":"e_1_2_6_35_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.10349"},{"key":"e_1_2_6_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20035"},{"key":"e_1_2_6_37_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.2001.4865"},{"key":"e_1_2_6_38_2","doi-asserted-by":"publisher","DOI":"10.1021\/jp961710n"},{"key":"e_1_2_6_39_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja9939385"},{"key":"e_1_2_6_40_2","doi-asserted-by":"publisher","DOI":"10.1021\/ci049938s"},{"key":"e_1_2_6_41_2","unstructured":"ChangCC LinCJ.LIBSVM: a library for support vector machine. 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