Molecular docking and QSAR studies of aromatase inhibitor androstenedione derivatives

Objectives  Aromatase (CYP19) inhibitors have emerged as promising candidates for the treatment of estrogen‐dependent breast cancer. In this study, a series of androstenedione derivatives with CYP19 inhibitory activity was subjected to a molecular docking study followed by quantitative structure–activity relationship (QSAR) analyses in search of ideal physicochemical characteristics of potential aromatase inhibitors.

[1]  K. Wähälä,et al.  The binding of lignans, flavonoids and coumestrol to CYP450 aromatase: A molecular modelling study , 2009, Molecular and Cellular Endocrinology.

[2]  S. Moslemi,et al.  Aromatase inhibitors: past, present and future , 2001, Molecular and Cellular Endocrinology.

[3]  M. Numazawa,et al.  Studies directed towards a mechanistic evaluation of inactivation of aromatase by the suicide substrates androsta-1,4-diene-3,17-diones and its 6-ene derivatives Aromatase inactivation by the 19-substituted derivatives and their enzymic aromatization , 2007, The Journal of Steroid Biochemistry and Molecular Biology.

[4]  Y. Ito,et al.  Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. , 1994, Endocrine reviews.

[5]  P. Roy,et al.  On Some Aspects of Variable Selection for Partial Least Squares Regression Models , 2008 .

[6]  R. Coombes,et al.  Phase I and endocrine study of exemestane (FCE 24304), a new aromatase inhibitor, in postmenopausal women. , 1992, Cancer research.

[7]  R. Santen,et al.  Letrozole (CGS 20267). A phase I study of a new potent oral aromatase inhibitor of breast cancer , 1995, Cancer.

[8]  Angelo Carotti,et al.  Three‐dimensional model of the human aromatase enzyme and density functional parameterization of the iron‐containing protoporphyrin IX for a molecular dynamics study of heme‐cysteinato cytochromes , 2006, Proteins.

[9]  C. Hasegawa,et al.  Structure–activity relationships of 2α-substituted androstenedione analogs as aromatase inhibitors and their aromatization reactions , 2005, The Journal of Steroid Biochemistry and Molecular Biology.

[10]  Kunal Roy,et al.  On Selection of Training and Test Sets for the Development of Predictive QSAR models , 2006 .

[11]  P. Goss.  Risks versus benefits in the clinical application of aromatase inhibitors. , 1999, Endocrine-related cancer.

[12]  M. Dowsett,et al.  ARIMIDEX™: A new oral, once-a-day aromatase inhibitor , 1995, The Journal of Steroid Biochemistry and Molecular Biology.

[13]  V. Njar,et al.  Aromatase inhibitors in advanced breast cancer: mechanism of action and clinical implications , 1998, The Journal of Steroid Biochemistry and Molecular Biology.

[14]  Yate-Ching Yuan,et al.  Molecular basis for the interaction of four different classes of substrates and inhibitors with human aromatase. , 2008, Biochemical pharmacology.

[15]  Shiuan Chen,et al.  Gene regulation studies of aromatase expression in breast cancer and adipose stromal cells , 1997, The Journal of Steroid Biochemistry and Molecular Biology.

[16]  G. Madhavi Sastry,et al.  Active site acidic residues and structural analysis of modelled human aromatase: A potential drug target for breast cancer , 2006, J. Comput. Aided Mol. Des..

[17]  P. Roy,et al.  Exploring the impact of size of training sets for the development of predictive QSAR models , 2008 .

[18]  R. Brueggemeier,et al.  7α-Arylaliphatic androsta-1,4-diene-3,17-diones as enzyme-activated irreversible inhibitors of aromatase , 1996, The Journal of Steroid Biochemistry and Molecular Biology.

[19]  W. Pangborn,et al.  Structural basis for androgen specificity and oestrogen synthesis in human aromatase , 2009, Nature.

[20]  Keiko Yamada,et al.  Structure–activity relationships of 3-deoxy androgens as aromatase inhibitors. synthesis and biochemical studies of 4-substituted 4-ene and 5-ene steroids , 2003, Steroids.

[21]  A. Howell,et al.  Advances in aromatase inhibition: clinical efficacy and tolerability in the treatment of breast cancer. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[22]  Kunal Roy,et al.  On further application of r  m2 as a metric for validation of QSAR models , 2009, Journal of Chemometrics.

[23]  Kunal Roy,et al.  On some aspects of validation of predictive quantitative structure–activity relationship models , 2007, Expert opinion on drug discovery.

[24]  Anton J. Hopfinger,et al.  Application of Genetic Function Approximation to Quantitative Structure-Activity Relationships and Quantitative Structure-Property Relationships , 1994, J. Chem. Inf. Comput. Sci..

[25]  H. J. Smith,et al.  Recent developments in aromatase inhibition as a potential treatment for oestrogen-dependent breast cancer. , 1989, Progress in medicinal chemistry.

[26]  J N Weinstein,et al.  Quantitative structure-antitumor activity relationships of camptothecin analogues: cluster analysis and genetic algorithm-based studies. , 2001, Journal of medicinal chemistry.

[27]  W. J. Langford.  Statistical Methods , 1959, Nature.

[28]  W. McGuire,et al.  The value of estrogen and progesterone receptors in the treatment of breast cancer , 1980, Cancer.

[29]  Y. Osawa,et al.  Purification of human placental aromatase cytochrome P-450 with monoclonal antibody and its characterization. , 1991, Biochemistry.

[30]  Yate-Ching Yuan,et al.  Molecular Characterization of Aromatase , 2009, Annals of the New York Academy of Sciences.

[31]  A. Ghose,et al.  Prediction of Hydrophobic (Lipophilic) Properties of Small Organic Molecules Using Fragmental Methods: An Analysis of ALOGP and CLOGP Methods , 1998 .

[32]  J. Potter,et al.  Aromatase Inhibitors: Current Indications and Future Prospects for Treatment of Postmenopausal Breast Cancer , 2004, Journal of the American Geriatrics Society.

[33]  P. Lønning.  Pharmacology of new aromatase inhibitors , 1996 .

[34]  A. Jones.  Prevention of breast cancer , 1991, Current opinion in oncology.

[35]  P. Goss,et al.  Estrogen and the risk of breast cancer. , 2001, The New England journal of medicine.

[36]  W. Dunn,et al.  Genetic Partial Least Squares in QSAR , 1996 .

[37]  L. Banting.  Inhibition of aromatase. , 1996, Progress in medicinal chemistry.

[38]  Kimito Funatsu,et al.  GA Strategy for Variable Selection in QSAR Studies: GA-Based PLS Analysis of Calcium Channel Antagonists , 1997, J. Chem. Inf. Comput. Sci..

[39]  Victor Guallar,et al.  Peripheral heme substituents control the hydrogen-atom abstraction chemistry in cytochromes P450 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[40]  R. Hartmann,et al.  CYP19 (aromatase): exploring the scaffold flexibility for novel selective inhibitors. , 2008, Bioorganic & medicinal chemistry.

[41]  C. Shapiro,et al.  Cyclooxygenase inhibitors suppress aromatase expression and activity in breast cancer cells. , 2005, The Journal of clinical endocrinology and metabolism.

[42]  Keiko Yamada,et al.  Synthesis and biochemical properties of 6-bromoandrostenedione derivatives with a 2,2-dimethyl or 2-methyl group as aromatase inhibitors. , 2004, Biological & pharmaceutical bulletin.

[43]  E. Simpson,et al.  A three‐dimensional model of aromatase cytochrome P450 , 1995, Protein science : a publication of the Protein Society.

[44]  S. Yamaguchi,et al.  6-Alkylandrosta-4,6-diene-3,17-diones and their 1,4,6-triene analogs as aromatase inhibitors Structure-activity relationships , 1997, Steroids.

[45]  Keiko Yamada,et al.  Probing the active site of aromatase with 2-methyl-substituted androstenedione analogs , 2003, Steroids.

[46]  M. A. Islam,et al.  Pharmacophore mapping of flavone derivatives for aromatase inhibition , 2008, Molecular Diversity.

[47]  P. Siiteri,et al.  Plasma precursors of estrogen. II. Correlation of the extent of conversion of plasma androstenedione to estrone with age. , 1974, The Journal of clinical endocrinology and metabolism.

[48]  Yate-Ching Yuan,et al.  Molecular basis for the aromatization reaction and exemestane-mediated irreversible inhibition of human aromatase. , 2007, Molecular endocrinology.

[49]  N. S. Murthy,et al.  Cancer epidemiology, prevention and control , 2004 .

[50]  K. Roy,et al.  On Two Novel Parameters for Validation of Predictive QSAR Models , 2009, Molecules.

[51]  M. Dowsett,et al.  Recent advances in the clinical application of aromatase inhibitors , 2001, The Journal of Steroid Biochemistry and Molecular Biology.

[52]  J. Kellis,et al.  Purification and characterization of human placental aromatase cytochrome P-450. , 1987, The Journal of biological chemistry.

[53]  P. Cole,et al.  Mechanism and inhibition of cytochrome P-450 aromatase. , 1990, Journal of medicinal chemistry.

[54]  Kunal Roy,et al.  Docking and 3D-QSAR studies of diverse classes of human aromatase (CYP19) inhibitors , 2010, Journal of molecular modeling.

[55]  Kunal Roy,et al.  Comparative QSAR Studies of CYP1A2 Inhibitor Flavonoids Using 2D and 3D Descriptors , 2008, Chemical biology & drug design.