Abstract
Aromatase (cytochrome 19) inhibitors have emerged as promising candidates for treatment of breast cancer. In search of potent aromatase inhibitors, docking and three-dimensional quantitative structure - activity relationship (3D-QSAR) studies using molecular shape, spatial, electronic, structural and thermodynamic descriptors have been performed on a diverse set of compounds having human aromatase inhibitory activities. An attempt has also been made to include two-dimensional (2D) descriptors in the QSAR studies. The chemometric tools used for model development are genetic function approximation (GFA) and genetic partial least squares (G/PLS). The docking study shows that the important interacting amino acids in the active site cavity are Met374, Arg115, Ile133, Ala306, Thr310, Asp309, Val370 and Ser478. One or more hydrogen bond formation with Met374 is one of the essential requirements for the ligands for optimum aromatase inhibition. The binding is further stabilized by van der Waals interactions with a few non-polar amino acid residues in the active site. The developed QSAR models indicate the importance of different shape, Jurs parameters, structural parameters, topological branching index and E-state index for different fragments. The results obtained from the QSAR analysis are supported by our docking observations. There should be one or two hydrogen bond acceptor groups (like –NO2, -CN) and optimal hydrophobicity for ideal aromatase inhibitors. A GFA model with spline option obtained using 3D descriptors was found to be the best model based on internal validation (Q2 = 0.668) while the best (externally) predictive model was a GFA model with spline option using combined set (2D and 3D) descriptors (R 2pred = 0.687). Based on r 2m (overall) criterion, the best model was a G/PLS model (using 3D descriptors) with spline option (r 2m (overall) = 0.606).
Similar content being viewed by others
References
Cancer facts and figures (2007) American Cancer Society: Atlanta, GA, 2007. http://www.cancer.org/downloads/STT/CAFF2007PWsecured.pdf (accessed on Nov 11, 2009)
Labrie F (1991) Intracrinology. Mol Cell Endocrinol 78:C113–C118. doi:10.1016/0303-7207(91)90116-A
Cuzick J, Wang DY, Bulbrook RD (1986) The prevention of breast cancer. Lancet 8472:83–86. doi:10.1016/S0140-6736(86)90729-4
Clemons M, Goss P (2001) Mechanisms of disease: estrogen and the risk of breast cancer. N Engl J Med 344:276–285. doi:10.1056/NEJM200101253440407
Osborne CK, Yochmowitz MG, Knight WA, McGuire WL (1980) The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancer 46:2884–2888. doi:10.1002/1097-0142(19801215)46:12+<2884::AID-CNCR2820461429>3.0.CO;2-U
Brueggemeier RW, Hackett JC, Diaz-Cruz ES (2005) Aromatase inhibitors in the treatment of breast cancer. Endocr Rev 26:331–345. doi:10.1210/er.2004-0015
Trunet PF, Vreeland F, Royce C, Chaudri HA, Cooper J, Bhatnagar AS (1997) Clinical use of aromatase inhibitors in the treatment of advanced breast cancer. J Steroid Biochem Mol Biol 61:241–245. doi:10.1016/S0960-0760(96)00249-X
Brodie AMH, Njar VCO (1998) Aromatase inhibitors in advanced breast cancer: mechanism of action and clinical implications. J Steroid Biochem Mol Biol 66:1–10. doi:10.1016/S0960-0760(98)00022-3
Banting L, Nicholls PJ, Shaw MA, Smith HJ (1989) Recent developments in aromatase inhibition as a potential treatment for oestrogen-dependent breast cancer. Prog Med Chem 26:253–298. doi:10.1016/S0079-6468(08)70242-X
Banting L (1996) Inhibition of aromatase. Prog Med Chem 33:147–184. doi:10.1016/S0079-6468(08)70305-9
O’Reilly JM, Brueggemeier RW (1996) 7alpha-arylaliphatic androsta-1,4-diene-3,17-diones as enzyme-activated irreversible inhibitors of aromatase. J Steroid Biochem Mol Bio l59:93–102. doi:10.1016/S0960-0760(96)00087-8
Santen RJ, Samojlik E, Lipton A, Harvey H, Ruby EB, Wells SA, Kendall J (1977) Kinetic, hormonal and clinical studies with aminoglutethimide in breast cancer. Cancer 39:2948–2958. doi:10.1002/1097-0142(197706)39:6<2948::AID-CNCR2820390681>3.0.CO;2-9
Plourde PV, Dyroff M, Dowsett M, Demers L, Yates R, Webster A (1995) ARIMIDEX: a new oral, once-a-day aromatase inhibitor. J Steroid Biochem Mol Biol 53:175–179. doi:10.1016/0960-0760(95)00045-2
Lipton A, Demers LM, Harvey HA, Kambic KB, Grossberg H, Brady C et al (1995) Letrozole (CGS 20267). A phase I study of a new potent oral aromatase inhibitor of breast cancer. Cancer 75:2132–2138. doi:10.1002/1097-0142(19950415)75:8<2132:AID-CNCR2820750816>3.0.CO;2-U
Evans TR, Di Salle E, Ornati G, Lassus M, Benedetti MS, Pianezzola E et al (1992) Phase I and endocrine study of exemestane (FCE 24304), a new aromatase inhibitor, inpostmenopausal women. Cancer Res 52:5933–5939
Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ et al (2003) A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793–1802. doi:10.1056/NEJMoa032312
Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T et al (2004) A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081–1092. doi:10.1056/NEJMoa040331
Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG et al (2002) Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 359:2131–2139. doi:10.1016/S0140-6736(02)09088-8
Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A et al (2000) Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a north american multicenter randomized trial. arimidex study group. J Clin Oncol 18:3758–3767
Arora A, Potter JF (2004) Aromatase inhibitors: current indications and future prospects for treatment of postmenopausal breast cancer. J Am Geriatr Soc 52:611–616. doi:10.1111/j.1532-5415.2004.52171.x
Goss PE (1999) Risks versus benefits in the clinical application of aromatase inhibitors. Endocr Relat Cancer 6:325–332. doi:10.1677/erc.0.0060325
Ghosh D, Griswold J, Erman M, Pangborn W (2009) Structural basis for androgen specificity and estrogen synthesis in human aromatase. Nature 457:219–223. doi:10.1038/nature07614
Favia AD, Cavalli A, Masetti M, Carotti A, Recanatini M (2006) Three-dimensional model of the human aromataseenzyme and density functional parameterization of the iron-containing protoporphyrin IX for a molecular dynamics study of heme-cysteinato cytochromes. Proteins 62:1074–1087. doi:10.1002/prot.20829
Hong Y, Yu B, Sherman M, Yuan YC, Zhou D, Chen S (2007) Molecular basis for the aromatization reaction and exemestane-mediated irreversible inhibition of human aromatase. Mol Endocrinol 21:401–414. doi:10.1210/me.2006-0281
Hong Y, Cho M, Yuan Y, Chen S (2008) Molecular basis for the interaction of four different classes of substrates and inhibitors with human aromatase. Biochem Pharmacol 75:1161–1169. doi:10.1016/j.bcp. 2007.11.010
Castellano S et al (2008) CYP19 (aromatase): Exploring the scaffold flexibility for novel selective inhibitors. Bioorg Med Chem 16:8349–8358. doi:10.1016/j.bmc.2008.08.046
Karkola S, Wähälä K (2009) The binding of lignans, flavonoids and coumestrol to CYP450 aromatase: A molecular modelling study. Mol Cell Endocrinol 301:235–244. doi:10.1016/j.mce.2008.10.003
Cole PA, Robinson CH (1990) Mechanism and Inhibition of Cytochrome P-450 Aromatase. J Med Chem 33:2933–2942. doi:10.1021/jm00173a001
Le Borgne M, Marchand P, Duflos M, Delevoye-Seiller B, Piessard-Robert S, Le Baut G, Hartmann RW, Palzer M (1997) Synthesis and in vitro evaluation of 3-(1-azolylmethy1)-1H-indoles and 3-(1-azolyl-l-phenylmethyl)-1H-indoles as inhibitors of P450 arom. Arch Pharm 330:141–145. doi:10.1002/ardp. 19973300506
Marchand P, Le Borgne M, Palzer M, Le Baut G, Hartmann RW (2003) Preparation and pharmacological profile of 7-(α-Azolylbenzyl)-1H-indoles and indolines as new aromatase inhibitors. Bioorg Med Chem Lett 13:1553–1555. doi:10.1016/S0960-894X(03)00182-3
Le Borgne M, Marchand P, Delevoye-Seiller B, Robert JM, Le Baut G, Hartmann RW, Palzer M (1999) New selective nonsteroidal aromatase inhibitors: synthesis and inhibitory activity of 2, 3 or 5-(α-azolylbenzyl)-1H-indoles. Bioorg Med Chem Lett 9:333–336. doi:10.1016/S0960-894X(98)00737-9
Hartmann RW, Palusczak A, Lacan F, Ricci G, Ruzziconi R (2004) CYP 17 and CYP 19 Inhibitors. Evaluation of fluorine effects on the inhibiting activity of regioselectively fluorinated 1-(Naphthalen-2-ylmethyl) imidazoles. J Enzyme Inhib Med Chem 19:145–155. doi:10.1080/147563604200196222
Sonnet P, Guillon J, Enguehard C, Dallemagne P, Bureau R, Rault S, Auvray P, Moslemi S, Sourdaine P, Galopin S, Séralini GE (1998) Design and synthesis of a new type of non steroidal human aromatase inhibitors. Bioorg Med Chem Lett 8:1041–1044. doi:10.1016/S0960-894X(98)00157-7
Recanatini M, Bisi A, Cavalli A, Belluti F, Gobbi S, Rampa A, Valenti P, Palzer M, Palusczak A, Hartmann RW (2001) A new class of nonsteroidal aromatase inhibitors: design and synthesis of chromone and xanthone derivatives and inhibition of the P450 enzymes aromatase and 17r-Hydroxylase/C17, 20-Lyase. J Med Chem 44:672–680. doi:10.1021/jm000955s
Cavalli A, Bisi A, Bertucci C, Rosini C, Paluszcak A, Gobbi S, Giorgio E, Rampa A, Belluti F, Piazzi L, Valenti P, Hartmann RW, Recanatini M (2005) Enantioselective nonsteroidal aromatase inhibitors identified through a multidisciplinary medicinal chemistry approach. J Med Chem 48:7282–7289. doi:10.1021/jm058042r
Leze MP, Le Borgne M, Pinson P, Palusczak A, Duflos M, Le Baut G, Hartmann RW (2006) Synthesis and biological evaluation of 5-[(aryl)(1H-imidazol-1-yl)methyl]-1H-indoles: Potent and selective aromatase inhibitors. Bioorg Med Chem Lett 16:1134–1137. doi:10.1016/j.bmcl.2005.11.099
Setzu MG, Stefancich G, Colla PL, Castellano S (2002) Synthesis and antifungal properties of N-[(1, 1?-biphenyl)-4-ylmethyl]-1H-imidazol-1-amine derivatives. Il Farmaco 57:1015–1018. doi:10.1016/S0014-827X(02)01294-6
Castellano S, Stefancich G, Chillotti A, Poni G (2003) Synthesis and antimicrobial properties of 3-aryl-1-(1, 1?-biphenyl-4-yl)-2-(1H-imidazol-1-yl)propanes as ‘carba-analogues’ of the Narylmethyl-N-[(1, 1?-biphenyl)-4-ylmethyl])-1H-imidazol-1-amines, a new class of antifungal agents. Il Farmaco 58:563–568. doi:10.1016/S0014-827X(03)00094-6
Castellano S, Colla PL, Musiu C, Stefancich G (2000) Azole antifungal agents related to naftifine and butenafine. Arch Pharm 333:162–166. doi:10.1002/1521-4184(20006)333:6<162::AID-ARDP162>3.0.CO;2-S
Castellano S, Stefancich G, Musiu C, Colla PL (2000) A new class of antifungal agents. Synthesis and antimycotic activity of disubstituted N-azolylamines. Archiv der Pharmazie 333:299–304. doi:10.1002/1521-4184(20009)333:9<299::AID-ARDP299>3.0.CO;2-F
Discovery Studio 2.1 is a product of Accelrys Inc, San Diego, CA, USA
Cerius2 Version 4.10 is a product of Accelrys Inc, San Diego, USA. http://www.accelrys.com/cerius2
Leonard JT, Roy K (2006) On selection of training and test sets for the development of predictive QSAR models. QSAR Comb Sci 25:235–251. doi:10.1002/qsar.200510161
Roy K, Mandal AS (2008) Development of linear and nonlinear predictive QSAR models and their external validation using molecular similarity principle for anti-HIV indolyl aryl sulfones. J Enz Inh Med Chem 23:980–995. doi:10.1080/14756360701811379
Hopfinger AJ, Tokarsi JS (1997) Three-dimensional Quantitative structure acticity relationship analysis. In: Charifson PS (ed) Practical Applications of Computer-Aided Drug Design. Dekker, New York, pp 105–164
Fan Y, Shi LM, Kohn KW, Pommier Y, Weinstein JN (2001) Quantitative structure-antitumor activity relationships of camptothecinanalogues: cluster analysis and genetic algorithm-based studies. J Med Chem 44:3254–3263. doi:10.1021/jm0005151
Rogers D, Hopfinger AJ (1994) Application of genetic function approximation to quantitative structure - activity relationship and quantitative structure - property relationship. J Chem Inf Comput Sci 34:854–866. doi:10.1021/ci00020a020
Dunn WJ III, Rogers D (1996) Genetic partial least squares in QSAR. In: Devillers J (ed) Genetic algorithms in molecular modeling. Academic, London, pp 109–130
Hasegawa K, Miyashita Y, Funatsu K (1997) GA strategy for variable selection in QSAR studies: GA-based PLS analysis of calcium channel antagonists. J Chem Inf Comput Sci 37:306–310. doi:10.1021/ci960047x
Snedecor GW, Cochran WG (1967) Statistical methods. Oxford & IBH, New Delhi
Wold S (1995) PLS for Multivariate Linear Modeling. In: van de Waterbeemd H (ed) Chemometric methods in molecular design. VCH, Weinheim, pp 195–218
Debnath AK (2001) In: Ghose AK, Viswanadhan VN (eds) Combinatorial library design and evaluation. Dekker, New York, pp 73–129
Roy K (2007) On Some aspects of validation of predictive QSAR models. Expert Opin Drug Discov 2:1567–1577. doi:10.1517/17460441.2.12.1567
Roy PP, Roy K (2008) On some aspects of variable selection for partial least squares regression models. QSAR Comb Sci 27:302–313. doi:10.1002/qsar.200710043
Roy K, Roy PP (2008) Comparative QSAR studies of CYP1A2 inhibitor flavonoids using 2D and 3D descriptors. Chem Biol Drug Des 72:370–382. doi:10.1111/j.1747-0285.2008.00717.x
Roy PP, Paul S, Mitra I, Roy K (2009) On two novel parameters for validation of predictive QSAR models. Molecules 14:1660–1701. doi:10.3390/molecules14051660
Mitra I, Roy PP, Kar S, Ojha P, Roy K (2010) On further application of r m 2 as a metric for validation of QSAR models. J Chemometrics 24:22–33. doi:10.1002/cem.1268
Roy PP, Leonard JT, Roy K (2008) Exploring the impact of the size of training sets for the development of predictive QSAR models. Chemom Intell Lab Sys 90:31–42. doi:10.1016/j.chemolab.2007.07.004
Murthy JN, Nagaraju M, Sastry GM, Rao AR, Sastry GN (2006) Active site acidic residues and structural analysis of modelled human aromatase: a potential drug target for breast cancer. J Comput Aided Mol Des 19:857–870. doi:10.1007/s10822-005-9024-0
Vanden Bossche H, Koymans L (1998) Cytochromes P450 in fungi. Mycoses 41:32–38. doi:10.1111/j.1439-0507.1998.tb00581.x
Eriksson L, Jaworska J, Worth AP, Cronin MT, McDowell RM, Gramatica P (2003) Methods for reliability and uncertainty assessment and for applicability evaluations of classification- and regression-based QSARs. Environ Health Perspect 111:1361–1375. doi:10.1289/ehp. 5758
Acknowledgments
This work is supported by a Major Research Project of the University Grants Commission (UGC), New Delhi. PPR thanks the UGC, New Delhi for a fellowship.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Roy, P.P., Roy, K. Docking and 3D-QSAR studies of diverse classes of human aromatase (CYP19) inhibitors. J Mol Model 16, 1597–1616 (2010). https://doi.org/10.1007/s00894-010-0667-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00894-010-0667-y