Abstract
Quantitative structure–activity relationships (QSAR) methods are urgently needed for predicting ADME/T (absorption, distribution, metabolism, excretion and toxicity) properties to select lead compounds for optimization at the early stage of drug discovery, and to screen drug candidates for clinical trials. Use of suitable QSAR models ultimately results in lesser time-cost and lower attrition rate during drug discovery and development. In the case of ADME/T parameters, drug metabolism is a key determinant of metabolic stability, drug–drug interactions, and drug toxicity. QSAR models for predicting drug metabolism have undergone significant advances recently. However, most of the models used lack sufficient interpretability and offer poor predictability for novel drugs. In this review, we describe some considerations to be taken into account by QSAR for modeling drug metabolism, such as the accuracy/consistency of the entire data set, representation and diversity of the training and test sets, and variable selection. We also describe some novel statistical techniques (ensemble methods, multivariate adaptive regression splines and graph machines), which are not yet used frequently to develop QSAR models for drug metabolism. Subsequently, rational recommendations for developing predictable and interpretable QSAR models are made. Finally, the recent advances in QSAR models for cytochrome P450-mediated drug metabolism prediction, including in vivo hepatic clearance, in vitro metabolic stability, inhibitors and substrates of cytochrome P450 families, are briefly summarized.
Similar content being viewed by others
References
van de Waterbeemd H, Gifford E (2003) Nat Rev Drug Discov 2:192. doi:10.1038/nrd1032
Fostel J (2005) Expert Opin Drug Metab Toxicol 1:565. doi:10.1517/17425255.1.3.565
Kola I, Landis J (2004) Nat Rev Drug Discov 3:711. doi:10.1038/nrd1470
Ruiz-Garcia A, Bermejo M, Moss A, Casabo VG (2007) J Pharm Sci [Epub ahead of print]
Li AP (2001) Drug Discov Today 6:357. doi:10.1016/S1359-6446(01)01712-3
Mager DE (2006) Adv Drug Deliv Rev 58:1326. doi:10.1016/j.addr.2006.08.002
Kumar GN, Surapaneni S (2001) Med Res Rev 21:397. doi:10.1002/med.1016
Fagerholm U (2007) J Pharm Pharmacol 59:803. doi:10.1211/jpp.59.6.0007
Yamashita F, Hashida M (2004) Drug Metab Pharmacokinet 19:327. doi:10.2133/dmpk.19.327
de Groot MJ, Kirton SB, Sutcliffe MJ (2004) Curr Top Med Chem 4:1803. doi:10.2174/1568026043387061
Zamora I, Afzelius L, Cruciani G (2003) J Med Chem 46:2313. doi:10.1021/jm021104i
Domanski TL, Halpert JR (2001) Curr Drug Metab 2:117. doi:10.2174/1389200013338612
Lewis DF (2002) Drug Metab Rev 34:55. doi:10.1081/DMR-120001390
Dai R, Pincus MR, Friedman FK (2000) Cell Mol Life Sci 57:487. doi:10.1007/PL00000709
De Rienzo F, Fanelli F, Menziani MC, De Benedetti PG (2000) J Comput Aided Mol Des 14:93. doi:10.1023/A:1008187802746
Sali A, Blundell TL (1993) J Mol Biol 234:779. doi:10.1006/jmbi.1993.1626
Shoichet BK, Kuntz ID (1993) Protein Eng 6:723. doi:10.1093/protein/6.7.723
Williams PA, Cosme J, Ward A, Angove HC, Matak Vinković D, Jhoti H (2003) Nature 424:464. doi:10.1038/nature01862
Jones JP, Mysinger M, Korzekwa KR (2002) Drug Metab Dispos 30:7. doi:10.1124/dmd.30.1.7
Singh SB, Shen LQ, Walker MJ, Sheridan RP (2003) J Med Chem 46:1330. doi:10.1021/jm020400s
Beck ME (2005) J Chem Inf Model 45:273. doi:10.1021/ci049687n
Korzekwa KR, Jones JP (1993) Pharmacogenetics 3:1. doi:10.1097/00008571-199302000-00001
Korhonen LE, Turpeinen M, Rahnasto M, Wittekindt C, Poso A, Pelkonen O et al (2007) Br J Pharmacol 150:932. doi:10.1038/sj.bjp.0707173
Kurogi Y, Güner OF (2001) Curr Med Chem 8:1035
Ekins S, Stresser DM, Williams JA (2003) Trends Pharmacol Sci 24:161. doi:10.1016/S0165-6147(03)00049-X
Hansch C, Fujita T (1964) J Am Chem Soc 86:1616. doi:10.1021/ja01062a035
Eriksson L, Johansson E, Müller M, Wold S (2000) J Chemometr 14:599. doi:10.1002/1099-128X(200009/12)14:5/6<599::AID-CEM619>3.0.CO;2-8
Refsgaard HH, Jensen BF, Christensen IT, Hagen N, Brockhoff PB (2006) Drug Dev Res 67:417. doi:10.1002/ddr.20108
Cronin MTD (2005) In: Helma C (ed) Predictive toxicology. Taylor & Francis Press, USA, p 93
Madden JC, Cronin MT (2006) Expert Opin Drug Toxicol 2:545. doi:10.1517/17425255.2.4.545
Di Marco A, Yao D, Laufer R (2003) Eur J Biochem 270:3768. doi:10.1046/j.1432-1033.2003.03763.x
McGinnity DF, Tucker J, Trigg S, Riley RJ (2005) Drug Metab Dispos 33:1700. doi:10.1124/dmd.105.005884
Zlokarnik G, Grootenhuis PD, Watson JB (2005) Drug Discov Today 10:1443. doi:10.1016/S1359-6446(05)03580-4
Cohen LH, Remley MJ, Raunig D, Vaz AD (2003) Drug Metab Dispos 31:1005. doi:10.1124/dmd.31.8.1005
Huebert ND, Dasgupta M, Chen Y (2004) Curr Opin Drug Discov Devel 7:69
Korfmacher WA (2003) Curr Opin Drug Discov Devel 6:481
Andersson TB, Bredberg E, Ericsson H, Sjöberg H (2004) Drug Metab Dispos 32:715. doi:10.1124/dmd.32.7.715
Clarke SE, Jeffrey P (2001) Xenobiotica 31:591. doi:10.1080/00498250110057350
Masimirembwa CM, Bredberg U, Andersson TB (2003) Clin Pharmacokinet 42:515. doi:10.2165/00003088-200342060-00002
Nagilla R, Frank KA, Jolivette LJ, Ward KW (2006) J Pharmacol Toxicol Methods 53:106. doi:10.1016/j.vascn.2005.08.005
Eriksson L, Jaworska J, Worth AP, Cronin MT, McDowell RM, Gramatica P (2003) Environ Health Perspect 111:1361
Golbraikh A, Tropsha A (2002) J Comput Aided Mol Des 16:357. doi:10.1023/A:1020869118689
Yasri A, Hartsough D (2001) J Chem Inf Comput Sci 41:1218. doi:10.1021/ci010291a
Kauffman GW, Jurs PC (2001) J Chem Inf Comput Sci 41:1553. doi:10.1021/ci010073h
Mattioni BE, Jurs PC (2002) J Chem Inf Comput Sci 42:94. doi:10.1021/ci0100696
Leach AR, Gillet VJ (2003) An introduction to chemoinformatics. Kluwer Academic Publisher, Boston, p 123
Daszykowski M, Walczak B, Massart DL (2002) Anal Chim Acta 468:91. doi:10.1016/S0003-2670(02)00651-7
Wang YH, Li Y, Yang SL, Yang L (2005) J Comput Aided Mol Des 19:137. doi:10.1007/s10822-005-3321-5
Leonard JT, Roy K (2006) QSAR Comb Sci 25:235. doi:10.1002/qsar.200510161
Schultz TW, Netzeva TI, Cronin MT (2003) SAR QSAR Environ Res 14:59. doi:10.1080/1062936021000058782
Rajer-Kanduc K, Zupan J, Majcen N (2003) Chemom Intell Lab Syst 65:221. doi:10.1016/S0169-7439(02)00110-7
Perez JJ (2005) Chem Soc Rev 34:143. doi:10.1039/b209064n
Maldonado AG, Doucet JP, Petitjean M, Fan BT (2006) Mol Divers 10:39. doi:10.1007/s11030-006-8697-1
Yap CW, Chen YZ (2005) J Chem Inf Model 45:982. doi:10.1021/ci0500536
Yap CW, Li ZR, Chen YZ (2006) J Mol Graph Model 24:383. doi:10.1016/j.jmgm.2005.10.004
Li ZR, Han LY, Xue Y, Yap CW, Li H, Jiang L et al (2007) Biotechnol Bioeng 97:389. doi:10.1002/bit.21214
Steinbeck C, Hoppe C, Kuhn S, Floris M, Guha R, Willighagen EL (2006) Curr Pharm Des 12:2111. doi:10.2174/138161206777585274
Tetko IV, Gasteiger J, Todeschini R, Mauri A, Livingstone D, Ertl P et al (2005) J Comput Aided Mol Des 19:453. doi:10.1007/s10822-005-8694-y
Dudek AZ, Arodz T, Gálvez J (2006) Comb Chem High Throughput Screen 9:213. doi:10.2174/138620706776055539
Akamatsu M (2002) Curr Top Med Chem 2:1381. doi:10.2174/1568026023392887
Cramer RD, Patterson DE, Bunce JD (1988) J Am Chem Soc 110:5959. doi:10.1021/ja00226a005
Klebe G, Abraham U, Mietzner T (1994) J Med Chem 37:4130. doi:10.1021/jm00050a010
Silverman BD, Platt DE (1996) J Med Chem 39:2129. doi:10.1021/jm950589q
Todeschini R, Lasagni M, Marengo E (1994) J Chemometr 8:263. doi:10.1002/cem.1180080405
Cruciani G, Crivori P, Carrupt P-A, Testa B (2000) J Mol Struct THEOCHEM 503:17. doi:10.1016/S0166-1280(99)00360-7
Crivori P, Zamora I, Speed B, Orrenius C, Poggesi I (2004) J Comput Aided Mol Des 18:155. doi:10.1023/B:JCAM.0000035184.11906.c2
Leardi R, Seasholtz MB, Pell RJ (2002) Anal Chim Acta 461:189. doi:10.1016/S0003-2670(02)00272-6
Bi J, Bennet K, Embrechts M, Breneman C, Song M (2003) J Mach Learn Res 3:1229. doi:10.1162/153244303322753643
Wegner JK, Fröhlich H, Zell A (2004) J Chem Inf Comput Sci 44:931. doi:10.1021/ci034233w
Xue CX, Zhang RS, Liu HX, Yao XJ, Liu MC, Hu ZD et al (2004) J Chem Inf Comput Sci 44:669. doi:10.1021/ci034248u
Guyon I, Weston J, Barnhill S, Vapnik V (2002) Mach Learn 46:389. doi:10.1023/A:1012487302797
Xue Y, Li ZR, Yap CW, Sun LZ, Chen X, Chen YZ (2004) J Chem Inf Comput Sci 44:1630. doi:10.1021/ci049869h
Xue Y, Yap CW, Sun LZ, Cao ZW, Wang JF, Chen YZ (2004) J Chem Inf Comput Sci 44:1497. doi:10.1021/ci049971e
Xue CX, Zhang RS, Liu HX, Yao XJ, Liu MC, Hu ZD et al (2004) J Chem Inf Comput Sci 44:1693. doi:10.1021/ci049820b
Xue CX, Zhang RS, Liu MC, Hu ZD, Fan BT (2004) J Chem Inf Comput Sci 44:950. doi:10.1021/ci034280o
Xue CX, Zhang RS, Liu HX, Liu MC, Hu ZD, Fan BT (2004) J Chem Inf Comput Sci 44:1267. doi:10.1021/ci049934n
Terfloth L, Gasteiger J (2001) Drug Discov Today 6:102. doi:10.1016/S1359-6446(01)00173-8
Baumann K (2003) Trends Analyt Chem 22:395. doi:10.1016/S0165-9936(03)00607-1
Baurin N, Mozziconacci JC, Arnoult E, Chavatte P, Marot C, Morin-Allory L (2004) J Chem Inf Comput Sci 44:276. doi:10.1021/ci0341565
Hemmateenejad B, Safarpour MA, Miri R, Nesari N (2005) J Chem Inf Model 45:190. doi:10.1021/ci049766z
Barrett SJ, Langdon WB (2005) In: Ashutosh T, Joshua K, Erel A, Keshav D, Rajkumar R (eds) Applications of soft computing: recent trends. Springer Publisher, p 99
Itskowitz P, Tropsha A (2005) J Chem Inf Model 45:777. doi:10.1021/ci049628±
Luke BT (1994) J Chem Inf Comput Sci 34:1279. doi:10.1021/ci00022a009
Izrailev S, Agrafiotis D (2001) J Chem Inf Comput Sci 41:176. doi:10.1021/ci000336s
Izrailev S, Agrafiotis DK (2002) SAR QSAR Environ Res 13:417. doi:10.1080/10629360290014296
Agrafiotis DK, Cedeño W (2002) J Med Chem 45:1098. doi:10.1021/jm0104668
Rogers D, Hopfinger AJ (1994) J Chem Inf Comput Sci 34:854. doi:10.1021/ci00020a020
Leardi R, Gonzalez AL (1998) Chemom Intell Lab Syst 41:195. doi:10.1016/S0169-7439(98)00051-3
Leardi R (2000) J Chemometr 14:643. doi:10.1002/1099-128X(200009/12)14:5/6<643::AID-CEM621>3.0.CO;2-E
Hashida M (2005) Yakugaku Zasshi 125:853. doi:10.1248/yakushi.125.853 Article in Japanese
Guangli M, Yiyu C (2006) J Pharm Pharm Sci 9:210
González MP, Caballero J, Tundidor-Camba A, Helguera AM, Fernández M (2006) Bioorg Med Chem 14:200. doi:10.1016/j.bmc.2005.08.009
Hemmateenejad B, Safarpour MA, Taghavi F (2003) J Mol Struct THEOCHEM 635:183. doi:10.1016/S0166-1280(03)00418-4
Hemmateenejad B (2005) Chemom Intell Lab Syst 75:231. doi:10.1016/j.chemolab.2004.09.005
Jalali-Heravi M, Kyani A (2007) Eur J Med Chem 42:649. doi:10.1016/j.ejmech.2006.12.020
Sutter JM, Dixon SL, Jurs PC (1995) J Chem Inf Comput Sci 35:77. doi:10.1021/ci00023a011
Zheng W, Tropsha A (2000) J Chem Inf Comput Sci 40:185. doi:10.1021/ci980033m
Blower P, Fligner M, Verducci J, Bjoraker J (2002) J Chem Inf Comput Sci 42:393. doi:10.1021/ci0101049
Ng C, Xiao Y, Putnam W, Lum B, Tropsha A (2004) J Pharm Sci 93:2535. doi:10.1002/jps.20117
Hasan M, AlKhamis T, Ali J (2000) Comput Ind Eng 38:323. doi:10.1016/S0360-8352(00)00043-7
Jung M, Tak J, Lee Y, Jung Y (2007) Bioorg Med Chem Lett 17:1082. doi:10.1016/j.bmcl.2006.11.022
Guha R, Jurs PC (2005) J Chem Inf Model 45:800. doi:10.1021/ci050022a
Guha R, Stanton DT, Jurs PC (2005) J Chem Inf Model 45:1109. doi:10.1021/ci050110v
Stanton DT (2003) J Chem Inf Comput Sci 43:1423. doi:10.1021/ci0340658
Dutta D, Guha R, Wild D, Chen T (2007) J Chem Inf Model 47:989. doi:10.1021/ci600563w
Guha R, Jurs PC (2004) J Chem Inf Comput Sci 44:2179. doi:10.1021/ci049849f
Jensen BF, Sørensen MD, Kissmeyer AM, Björkling F, Sonne K, Engelsen SB et al (2003) J Comput Aided Mol Des 17:849. doi:10.1023/B:JCAM.0000021861.31978.da
Duchowicz PR, González MP, Helguera AM, Dias Soeiro Cordeiro MN, Castro EA (2007) Chemom Intell Lab Syst 88:197. doi:10.1016/j.chemolab.2007.05.001
Fox T, Kriegl JM (2006) Curr Top Med Chem 6:1579. doi:10.2174/156802606778108915
Arimoto R (2006) Curr Top Med Chem 6:1609. doi:10.2174/156802606778108951
Yap CW, Xue Y, Li ZR, Chen YZ (2006) Curr Top Med Chem 6:1593. doi:10.2174/156802606778108942
Jolivette LJ, Ekins S (2007) Adv Clin Chem 43:131. doi:10.1016/S0065-2423(06)43005-5
Hudelson MG, Jones JP (2006) J Med Chem 49:4367. doi:10.1021/jm0601553
Jensen BF, Vind C, Padkjaer SB, Brockhoff PB, Refsgaard HH (2007) J Med Chem 50:501. doi:10.1021/jm060333s
Breiman L (2001) Mach Learn 45:5. doi:10.1023/A:1010933404324
Svetnik V, Liaw A, Tong C, Culberson JC, Sheridan RP, Feuston BP (2003) Chem Inf Comput Sci 43:1947. doi:10.1021/ci034160g
Lombardo F, Obach RS, Dicapua FM, Bakken GA, Lu J, Potter DM et al (2006) J Med Chem 49:2262. doi:10.1021/jm050200r
Zhang QY, Aires-de-Sousa J (2007) J Chem Inf Model 47:1. doi:10.1021/ci050520j
Bruce CL, Melville JL, Pickett SD, Hirst JD (2007) J Chem Inf Model 47:219. doi:10.1021/ci600332j
Sakiyama Y, Yuki H, Moriya T, Hattori K, Suzuki M, Shimada K, Honma T (2007) J Mol Graph Model 27. doi:10.1016/j.jmgm.2007.06.005
Breiman L (1996) Mach Learn 24:123
Schapire RE, Freund Y, Bartlett P, Lee WS (1998) Ann Statist 26:1651. doi:10.1214/aos/1024691352
Koike A (2006) SAR QSAR Environ Res 17:497. doi:10.1080/10629360600934168
Svetnik V, Wang T, Tong C, Liaw A, Sheridan RP, Song Q (2005) J Chem Inf Model 45:786. doi:10.1021/ci0500379
Ren S, Kim H (2003) J Chem Inf Comput Sci 43:2106. doi:10.1021/ci034092y
Ren S (2003) J Chem Inf Comput Sci 43:1679. doi:10.1021/ci034046y
Xu QS, Daszykowski M, Walczak B, Daeyaert F, de Jonge MR, Heeres J et al (2004) Chemom Intell Lab Syst 72:27. doi:10.1016/j.chemolab.2004.02.007
Xu QS, Daeyaert F, Lewi PJ, Massart DL (2006) Chemom Intell Lab Syst 82:24. doi:10.1016/j.chemolab.2005.07.005
Put R, Xu QS, Massart DL, Vander Heyden Y (2004) J Chromatogr A 1055:11. doi:10.1016/j.chroma.2004.07.112
Choua SM, Leeb TS, Shaoc YE, Chen IF (2004) Expert Syst Appl 27:133. doi:10.1016/j.eswa.2003.12.013
Deconinck E, Xu QS, Put R, Coomans D, Massart DL, Vander Heyden Y (2005) J Pharm Biomed Anal 39:1021. doi:10.1016/j.jpba.2005.05.034
Deconinck E, Ates H, Callebaut N, Van Gyseghem E, Vander Heyden Y (2007) J Chromatogr A 1138:190. doi:10.1016/j.chroma.2006.10.068
Deconinck E, Coomans D, Vander Heyden Y (2007) J Pharm Biomed Anal 43:119. doi:10.1016/j.jpba.2006.06.022
Goulon A, Picot T, Duprat A, Dreyfus G (2007) SAR QSAR Environ Res 18:141. doi:10.1080/10629360601054313
Schneider G, Coassolo P, Lavé T (1999) J Med Chem 42:5072. doi:10.1021/jm991030j
Zuegge J, Schneider G, Coassolo P, Lavé T (2001) Clin Pharmacokinet 40:553. doi:10.2165/00003088-200140070-00006
Lee S, Kim D (2007) Arch Pharm Res 30:182
Lee PH, Cucurull-Sanchez L, Lu J, Du YJ (2007) J Comput Aided Mol Des [Epub ahead of print]
Molnar L, Keseru GM (2002) Bioorg Med Chem Lett 12:419. doi:10.1016/S0960-894X(01)00771-5
Ekins S, Berbaum J, Harrison RK (2003) Drug Metab Dispos 31:1077. doi:10.1124/dmd.31.9.1077
Wanchana S, Yamashita F, Hashida M (2003) Pharm Res 20:1401. doi:10.1023/A:1025702009611
Merkwirth C, Mauser H, Schulz-Gasch T, Roche O, Stahl M, Lengauer T (2004) J Chem Inf Comput Sci 44:1971. doi:10.1021/ci049850e
Kriegl JM, Arnhold T, Beck B, Fox T (2005) QSAR Comb Sci 24:491. doi:10.1002/qsar.200430925
Arimoto R, Prasad MA, Gifford EM (2005) J Biomol Screen 10:97. doi:10.1177/1087057104274091
Zhou DS, Liu RF, Otmani SA, Grimm SW, Zauhar RJ, Zamora I (2007) Lett Drug Des Discov 4:192. doi:10.2174/157018007780077462
Susnow RG, Dixon SL (2003) J Chem Inf Comput Sci 43:1308. doi:10.1021/ci030283p
O’Brien SE, de Groot MJ (2005) J Med Chem 48:1287. doi:10.1021/jm049254b
Chohan KK, Paine SW, Mistry J, Barton P, Davis AM (2005) J Med Chem 48:5154. doi:10.1021/jm048959a
Burton J, Ijjaali I, Barberan O, Petitet F, Vercauteren DP, Michel A (2006) J Med Chem 49:6231. doi:10.1021/jm060267u
Manga N, Duffy JC, Rowe PH, Cronin MT (2005) SAR QSAR Environ Res 16:43. doi:10.1080/10629360412331319871
Terfloth L, Bienfait B, Gasteiger J (2007) J Chem Inf Model 47:1688. doi:10.1021/ci700010t
Jones JP, Shou M, Korzekwa KR (1996) Adv Exp Med Biol 387:355
Cruciani G, Carosati E, De Boeck B, Ethirajulu K, Mackie C, Howe T et al (2005) J Med Chem 48:6970. doi:10.1021/jm050529c
Zhou D, Afzelius L, Grimm SW, Andersson TB, Zauhar RJ, Zamora I (2006) Drug Metab Dispos 34:976
de Graaf C, Oostenbrink C, Keizers PH, van der Wijst T, Jongejan A, Vermeulen NP (2006) J Med Chem 49:2417. doi:10.1021/jm0508538
Sheridan RP, Korzekwa KR, Torres RA, Walker MJ (2007) J Med Chem 50:3173. doi:10.1021/jm0613471
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Li, H., Sun, J., Fan, X. et al. Considerations and recent advances in QSAR models for cytochrome P450-mediated drug metabolism prediction. J Comput Aided Mol Des 22, 843–855 (2008). https://doi.org/10.1007/s10822-008-9225-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10822-008-9225-4