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Integrating Crystallography into Early Metabolism Studies

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From Molecules to Medicines

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Abstract

Since bioavailability, activity, toxicity, distribution, and final elimination all depend on metabolic biotransformations, it would be extremely advantageous if this information to be produced early in the discovery phase. Once obtained, researchers can judge whether or not a potential candidate should be eliminated from the pipeline, or modified to improve chemical stability or safety. The use of in silico methods to predict the site of metabolism in Phase I cytochrome-mediated reactions is a starting point in any metabolic pathway prediction. This paper presents a new method, which provides the site of metabolism for any CYP-mediated reaction acting on unknown substrates. The methodology can be applied automatically to all the cytochromes whose Xray 3D structure is known, but can be also applied to homology model 3D structures. The fully automated procedure can be used to detect positions that should be protected in order to avoid metabolic degradation, or to check the suitability of a new scaffold or pro-drug. Therefore the procedure is also a valuable new tool in early ADME-Tox, where drug-safety and metabolic profile patterns must be evaluated as soon, and as early, as possible.

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References

  1. R. Iyer and D. Zhang, in Drug metabolism in drug design and development, D. Zhang, M. Zhu, W.G. Humphreys Eds, Wiley 2008, p. 267.

    Google Scholar 

  2. M. Zhu, W. Zhao, W. G. Humphreys, in Drug metabolism in drug design and development, D. Zhang, M. Zhu, W.G. Humphreys Eds, Wiley 2008, pp. 287–313.

    Google Scholar 

  3. M. Ablström, M. Ridderström, K. Luthman, I. Zamora, J. Med Chem. 50(18), 4444– 4452 (2007).

    Article  Google Scholar 

  4. M. Rowley, D.J. Hallett, S. Goodacre, C. Moyes, J. Crawforth, T.J. Sparey, Sm. Patel, R. Marwood, Sh. Patel, S. Thomas, L. Hitzel, D. O'Connor, N. Szeto, J.L. Castro, P.H. Hutson, A.M. MacLeod, J. Med. Chem. 44(10), 1603–1614 (2001).

    Article  Google Scholar 

  5. I. Zamora, L. Afzelius, G. Cruciani, J. Med. Chem. 46, 2313–2324 (2003).

    Article  Google Scholar 

  6. G. Berellini, G. Cruciani, R. Mannhold, J. Med. Chem. 48(13), 4389–4399 (2005).

    Article  Google Scholar 

  7. G. Cruciani, E. Carosati, B. De Boeck, K. Ethirajulu, C. Makie, T. Howe, R. Vianello, J. Med. Chem. 48(7), 2445–2456 (2005).

    Article  Google Scholar 

  8. Hasselgren-Arnby C, Smith J, Glen RC, and Boyer S (2005) SPORCalc-fingerprint based probabilistic scoring of metabolic sites, in The 7th International Conference on Chemical Structures. 5–9 Jun, 2005; Abstract C-2; Noordwijkerhout, The Netherlands.

    Google Scholar 

  9. M.J. De Groot, M. Ackland, V. Horne, A. Alexander, J. Barry, J. Med. Chem. 42, 4062–4070 (1999).

    Article  Google Scholar 

  10. B.C. Jones, G. Hawksworth, V.A. Horne, A. Newlands, J. Morsman, M.S. Tute, D.A. Smith, Drug Metab. Disp. 24, 260–266 (1996).

    Google Scholar 

  11. S.B. Singh, L.Q. Shen, M.J. Walker, R. Sheridan, J. Med. Chem. 46, 1330–1336 (2003).

    Article  Google Scholar 

  12. H. Chen, M. de Groot, N. Vermulen, R.P. Hanzlik, J. Org. Chem. 62, 8227–8230 (1997).

    Article  Google Scholar 

  13. S.P. Visser, F. Ogliaro, P.K. Sharma, S. Shaik, J. Am. Chem. Soc. 124, 11809–11826 (2002).

    Article  Google Scholar 

  14. K.R. Korzekwa, J. Grogan, S. DeVito, J.P. Jones, Adv. Expl. Med. Biol. 38, 361–369 (1996).

    Google Scholar 

  15. D.F. Lewis, M. Dickins, P.J. Eddershaw, M.H. Tarbit, P.S. Goldfarb, Drug Metab. Drug Interac. 15, 1–49 (1999).

    Google Scholar 

  16. A. Mancy, P. Broto, S. Dijols, P.M. Dansette, D. Mansuy, Biochemistry 34, 10365–10375 (1995).

    Article  Google Scholar 

  17. M. Riddestrom, I. Zamora, O. Fjäström, T.B. Andersson, J. Med. Chem. 44, 4072–4081 (2001).

    Article  Google Scholar 

  18. F. Darvas, S. Marokhazi, P. Kormos, G. Kulkarmi, H. Kalasz, A. Papp, in: Drug Metabolism; Erhardt, P.W. Ed., Blackwell Science, 1999, pp 237–270.

    Google Scholar 

  19. B. Testa, A.L. Balmat, A. Long, P. Judson, Chem Biodivers. 2, 872–885 (2005).

    Article  Google Scholar 

  20. Open-shell radicals were optimized at AM1 semi-empirical level. Single point energy evaluations were performed by DFT at the B3LYP/6-311G** level of theory since correlation between experimental and calculated radical stabilities resulted in reasonable agreement for this level of theory.

    Google Scholar 

  21. S. Kudo, M. Uchida, M. Odomi, Eur. J. Clin. Pharm. 52, 479–485 (1997).

    Article  Google Scholar 

  22. J.F. Pritchard, Semin. Oncol. 19, 9–15 (1992).

    MathSciNet  Google Scholar 

  23. C. de Graaf, N.P.E. Vermeulen, K.A. Feenstra, J. Med. Chem. 48, 2725–2755 (2005).

    Article  Google Scholar 

  24. S. Katsuhisa, I. Yuji, O. Shinji, H. Yusuke, K. Shosuke, Mutat. Res. 565, 35–44 (2004).

    Google Scholar 

  25. M.R. Wester, J.K. Yano, G.A. Schoch, K.J. Griffin, C.D. Stout, E.F. Johnson, http://www.pdb.org, 2004, 1R9O entry.

  26. J.K. Yano, M.R. Wester, G.A. Schoch, K.J. Griffin, C.D. Stout, E.F. Johnson, http://www.pdb.org, 2004, 1TQN entry

  27. L. Afzelius, C.H. Arnby, A. Broo, L. Carlsson, C. Isaksson, U. Jurva, B. Kjellander, K. Kolmodin, K. Nilsson, F. Raubacher, L. Weildolf, Drug Metab. Rev. 39(1), 61–86 (2007).

    Article  Google Scholar 

  28. S.R. Thomas, U. Gerhard, J. Mass Spectrom. 39, 942–948 (2004).

    Article  Google Scholar 

  29. E. Kantharaj, A. Tuytelaars, P. Proost, Z. Ongel, H.P. Assouw, R.A. Gilissen, Rapid Commun. Mass Sp. 17, 2661–2668 (2003).

    Article  Google Scholar 

  30. R. Kostiainen, T. Kotiano, T. Kuurama, S.J. Auriola, Mass. Spectrom. 38, 357–372 (2003).

    Article  Google Scholar 

  31. O. Corcoran, M. Spraul, Drug Discov. Today 8, 624–631 (2003).

    Article  Google Scholar 

  32. A.E.F. Nassar, R. E. Talaat, Drug Discov. Today 9, 317–327 (2004).

    Article  Google Scholar 

  33. P.J. Goodford, J. Med. Chem. 28, 849–857 (1985).

    Article  Google Scholar 

  34. E. Carosati, S. Sciabola, G. Cruciani, J. Med. Chem. 47, 5114–5125 (2004).

    Article  Google Scholar 

  35. P.J. Goodford, in Rational Molecular Design in Drug Research, Alfred Benzon Symposium 42, Liljefors, T., Jorgensen, F.S., Krogsgaard-Larsen, P. Eds.; Munkgaard, Copenhagen 1998, pp. 215–230.

    Google Scholar 

  36. MetaSite ver. 3.0, Molecular Discovery Ltd, 2008 (http://www.moldiscovery.com)

  37. U. Trinks, E. Buchdunger, P. Furet, W. Kump, H. Mett, T. Meyer, M. Muller, U. Regenass, G. Rihs, N. Lydon, J. Med. Chem. 37, 1015–1027 (1994).

    Article  Google Scholar 

  38. S.B. Rosemblum, T. Huynh, A. Afonso, H.R. Davis, N. Yumibe, J.W. Clader, D. Burnett, J. Med. Chem. 41, 973–980 (1998).

    Article  Google Scholar 

  39. D. Zhou, A. Afzelius, S.W. Grimm, T.B. Andersson, R.J. Zauhar, I. Zamora, Drug Metab. Dispos. 34, 976–983 (2006).

    Google Scholar 

  40. F. De Rienzo, F. Fanelli, M.C. Menziani, P.G. De Benedetti. J. Comp.-Aided Mol. Des. 14, 93–116 (2000).

    Article  Google Scholar 

  41. I. Zamora, in Antitargets, R.J. Vaz and T. Klabunde Eds, Wiley-VCH 2008, pp. 247–265.

    Google Scholar 

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Author information

Authors and Affiliations

  1. Laboratory for Chemometrics and Cheminformatics, Chemistry Department, University of Perugia, Via Elce di sotto 10, Perugia, Italy

    Gabriele Cruciani, Yasmin Aristei, Laura Goracci & Emanuele Carosati

Authors
  1. Gabriele Cruciani
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  2. Yasmin Aristei
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  3. Laura Goracci
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  4. Emanuele Carosati
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Editor information

Editors and Affiliations

  1. Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel

    Joel L. Sussman

  2. Department of Chemical Sciences, University of Padova, Italy

    Paola Spadon

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Cruciani, G., Aristei, Y., Goracci, L., Carosati, E. (2009). Integrating Crystallography into Early Metabolism Studies. In: Sussman, J.L., Spadon, P. (eds) From Molecules to Medicines. NATO Science for Peace and Security Series A: Chemistry and Biology. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-2339-1_5

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