Summary
Human 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes the interconversion of cortisone into active cortisol. 11βHSD1 inhibition is a tempting target for the treatment of a host of human disorders that might benefit from blockade of glucocorticoid action, such as obesity, metabolic syndrome, and diabetes type 2. Here, we report an in silico screening study aimed at identifying new selective inhibitors of human 11βHSD1 enzyme. In the first step, homology modeling was employed to build the 3D structure of 11βHSD1. Further, molecular docking was used to validate the predicted model by showing that it was able to discriminate between known 11βHSD1 inhibitors or substrates and non-inhibitors. The homology model was found to reproduce closely the crystal structure that became publicly available in the final stages of this work. Finally, we carried out structure-based virtual screening experiments on both the homology model and the crystallographic structure with a database of 114’000 natural molecules. Among these, 15 molecules were consistently selected as inhibitors based on both the model and crystal structures of the enzyme, implying a good quality for the homology model. Among these putative 11βHSD1 inhibitors, two were flavonone derivatives that have already been shown to be potent inhibitors of the enzyme.
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Bjorntorp P., Obesity, (1997). Lancet 350:423
Zimmet P., Alberti K.G., Shaw J., (2001) Nature 414:782
Ricketts M.L., Shoesmith K.J., Hewison M., Strain A., Eggo M.C., Stewart P.M., (1998) J. Endocrinol. 156:159
Tomlinson J.W., Walker E.A., Bujalska I.J., Draper N., Lavery G.G., Cooper M.S., Hewison M., Stewart P.M., (2004) Endocrine Rev. 25:831
Agarwal A.K., Monder C., Eckstein B., White P.C., (1989) J. Biol. Chem. 264:18939
Engeli S., Bohnke J., Feldpausch M., Gorzelniak K., Heintze U., Janke J., Luft F.C., Sharma A.M., (2004) Obes. Res. 12:9
Masuzaki H., Paterson J., Shinyama H., Morton N.M., Mullins J.J., Seckl J.R., Flier J.S., (2001) Science, 294:2166
Kotelevtsev Y., Holmes M.C., Burchell A., Houston P.M., Schmoll D., Jamieson P., Best R., Brown R., Edwards C.R., Seckl J.R., Mullins J.J., (1997) Proc. Natl. Acad. Sci. USA, 94:14924
Morton N.M., Holmes M.C., Fievet C., Staels B., Tailleux A., Mullins J.J., Seckl J.R., (2001) J. Biol. Chem., 276:41293
Agarwal A.K., Rogerson F.M., Mune T., White P.C., (1995) Genomics 29:195
Obeid J., White P.C., (1992) Biochem. Biophys. Res. Commun. 188:222
Berman H.M., Westbrook J., Feng Z., Gilliland G., Bhat T.N., Weissig H., Shindyalov I.N., Bourne P.E., (2000) Nucleic Acids Res. 28:235
Benach J., Filling C., Oppermann U.C., Roversi P., Bricogne G., Berndt K.D., Jornvall H., Ladenstein R., (2002) Biochemistry 41:14659
Ghosh D., M. Erman, Z. Wawrzak, W.L. Duax, W. Pangborn, 1994. Structure, 2:973–980
Nakajima K., Yamashita A., Akama H., Nakatsu T., Kato H., Hashimoto T., Oda J., Yamada Y., (1998) Proc. Natl. Acad. Sci. USA 95:4876
Blum A., Raum A., Maser E., (2003) Biochemistry, 42:4108
Moore J.S., Monson J.P., Kaltsas G., Putignano P., Wood P.J., Sheppard M.C., Besser G.M., Taylor N.F., Stewart P.M., (1999) J. Clin. Endocrinol. Metab. 84:4172
Morton N.M., Paterson J.M., Masuzaki H., Holmes M.C., Staels B., Fievet C., Walker B.R., Flier J.S., Mullins J.J., Seckl J.R., (2004) Diabetes, 53:931
Barf T., Vallgarda J., Emond R., Haggstrom C., Kurz G., Nygren A., Larwood V., Mosialou E., Axelsson K., Olsson R., Engblom L., Edling N., Ronquist-Nii Y., Ohman B., Alberts P., Abrahmsen L., (2002) J. Med. Chem. 45:3813
Schweizer R.A.S., Atanasov A.G., Frey B.M., Odermatt A., (2003) Molecular and Cellular Endocrinology 212:41
Ginalski K., Pas J., Wyrwicz L.S., von Grotthuss M., Bujnicki J.M., Rychlewski L. (2003) Nucleic Acids Res. 31:3804
Shi J., Blundell T.L., Mizuguchi K., (2001) J. Mol. Biol. 310:243
Rychlewski L., Jaroszewski L., Li W., Godzik A., (2000) Protein Sci. 9:232
McGuffin L.J., Jones D.T., (2003) Bioinformatics, 19:874
Vriend G., (1990) J. Mol. Graph. 8:52
Sybyl, Version 7.0, Tripos Inc, St. Louis, MO, 2004
GOLD, Version 2.1, CCDC Software Limited, Cambridge, 2003
Glide, Version 3.5, Schrödinger Inc, Portland, 2004
Hosfield D.J., Wu Y., Skene R.J., Hilgers M., Jennings A., Snell G.P., Aertgeerts K., (2005) J. Biol. Chem. 280:4639
Jones G., Willett P., Glen R.C., (1995) J. Mol. Biol. 245:43
Jones G., Willett P., Glen R.C., Leach A.R., Taylor A.R., (1997) J. Mol. Biol., 267:727
Friesner R.A., Banks J.L., Murphy R.B., Halgren T.A., Klicic J.J., Mainz D.T., Repasky M.P., Knoll E.H., Shelley M., Perry J.K., Shaw D.E., Francis P., Shenkin P.S., (2004) J. Med. Chem., 47:1739
Eldridge M.D., Murray C.W., Auton T.R., Paolini G.V., Mee R.P., (1997) J. Comput-Aided Mol. Des. 11:425
Berger J., Tanen M., Elbrecht A., Hermanowski-Vosatka A., Moller D.E., Wright S.D., Thieringer R., (2001) J. Biol. Chem., 276:12629
Barton, P.J., Clarke, D.S., Davies, C.D., Hargreaves, R.B., Pease, J.E. and Rankine, M.T., PCT Int. Appl. WO 2004011410, 2004
Morris, D.J. and Brem, A.S., PCT Int. Appl. WO 2003059267, 2003
Olson, S.H., Balkovec, J.M. and Zhu, Y., PCT Int. Appl. WO 2003059267, 2003
SciFinder, 2004 Edition, American Chemical Society, 2004
Ohlson T., Bjorn W., Elofsson A., (2004) Proteins 57:188
Zhang Z., Kochhar S., Grigorov M.G., (2005). Protein Sci., 14:431
Sali A., Blundell T.L., (1993) J. Mol. Biol. 234:779
Schwede T., Kopp J., Guex N., Peitsch M.C., (2003) Nuclei Acids Res. 31:3381
Bates, P.A., Kelley, L.A., MacCallum, R.M. and Sternberg, M.J.E., Proteins, Suppl 5 (2001) 39
Marti-Renom M.A., Stuart A., Fiser A., Sanchez R., Melo F., Sali A., (2000) Annu. Rev. Biophys. Biomol. Struct. 29:219
Laskowski R.A., MacArthur M.W., Moss D.S., Thornton J.M., (1993) J. Appl. Cryst. 26:283
Ogg D., Elleby B., Norstrom C., Stefansson K., Abrahmsen L., Oppermann U., Svensson S., (2004) J. Biol. Chem., 280:3789
Shindyalov I.N., Bourne P.E., (1998) Protein Eng. 11:739
Kopp J., Schwede T., (2004) Pharmacogenomics 5:405
Murzin A.G., Brenner S.E., Hubbard T., Chothia C., (1995) J. Mol. Biol. 247:536
Russell R.B., Alber F., Aloy P., Davis F.P., Korkin D., Pichaud M., Topf M., Sali A., (2004) Curr. Opin. Struct. Biol. 14:313
Zhang Y., Skolnick J., (2005) Proc. Natl. Acad. Sci. USA 102:1029
Kellenberger E., Rodrigo J., Muller P., Rognan D., (2004) Proteins 57:225
Perola E., Walters W.P., Charifson P.S., (2004) Proteins 56:235
Krovat, E.M., Steindl, T. and Langer, T., (2005) Curr. Comp. Aided Drug Des. 1: 93
Friesner R.A., Banks J.L., Murphy R.B., Halgren T.A., Klicic J.J., Mainz D.T., Repasky M.P., Knoll E.H., Shelley M., Perry J.K., Shaw D.E., Francis P., Shenkin P.S., (2004) J. Med. Chem. 47:1739
Halgren T.A., Murphy R.B., Friesner R.A., Beard H.S., Frye L.L., Pollard W.T., Banks J.L., (2004) J. Med. Chem. 47:1750
Lipinski C.A., (2001) J. Pharm. Toxicol. Meth. 44:235
Acknowledgements
We thank Dr. Catherine Mace and Dr. Christian Darimont for bringing to our attention the importance of the subject as well as for the numerous discussions we had on the topic. We thank also both reviewers for their constructive comments and suggestions that helped us to improve the quality of our work.
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Miguet, L., Zhang, Z., Barbier, M. et al. Comparison of a homology model and the crystallographic structure of human 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in a structure-based identification of inhibitors. J Comput Aided Mol Des 20, 67–81 (2006). https://doi.org/10.1007/s10822-006-9037-3
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DOI: https://doi.org/10.1007/s10822-006-9037-3