Structure Guided Molecular Docking Assisted Alignment Dependent 3DQSAR Study on Steroidal Aromatase Inhibitors (SAIs) as Anti-breast Cancer Agents

Author(s): Laxmi Banjare, Sant Kumar Verma, Akhlesh Kumar Jain, Suresh Thareja*.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 7 , 2019

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Graphical Abstract:


Abstract:

Background: In spite of the availability of various treatment approaches including surgery, radiotherapy, and hormonal therapy, the steroidal aromatase inhibitors (SAIs) play a significant role as chemotherapeutic agents for the treatment of estrogen-dependent breast cancer with the benefit of reduced risk of recurrence. However, due to greater toxicity and side effects associated with currently available anti-breast cancer agents, there is emergent requirement to develop target-specific AIs with safer anti-breast cancer profile.

Methods: It is challenging task to design target-specific and less toxic SAIs, though the molecular modeling tools viz. molecular docking simulations and QSAR have been continuing for more than two decades for the fast and efficient designing of novel, selective, potent and safe molecules against various biological targets to fight the number of dreaded diseases/disorders. In order to design novel and selective SAIs, structure guided molecular docking assisted alignment dependent 3D-QSAR studies was performed on a data set comprises of 22 molecules bearing steroidal scaffold with wide range of aromatase inhibitory activity.

Results: 3D-QSAR model developed using molecular weighted (MW) extent alignment approach showed good statistical quality and predictive ability when compared to model developed using moments of inertia (MI) alignment approach.

Conclusion: The explored binding interactions and generated pharmacophoric features (steric and electrostatic) of steroidal molecules could be exploited for further design, direct synthesis and development of new potential safer SAIs, that can be effective to reduce the mortality and morbidity associated with breast cancer.

Keywords: Aromatase, breast cancer, 3D-QSAR, molecular docking, steroidal aromatase inhibitors, steric and electrostatic.

[1]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics. CA Cancer J. Clin., 2015, 65(1), 5-29.
[2]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics. CA Cancer J. Clin., 2017, 67(1), 7-30.
[3]
Tazhibi, M.; Feizi, A. Awareness levels about breast cancer risk factors, early warning signs, and screening and therapeutic approaches among Iranian adult women: A large population based study using latent class analysis. BioMed Res. Int., 2014, 2014, 1-9.
[4]
Downs-Holmes, C.; Silverman, P. Breast cancer: Overview and updates. Nurse Pract., 2011, 36(12), 20-26.
[5]
Khokhar, A. Breast cancer in India: Where do we stand and where do we go. Asian Pac. J. Cancer Prev., 2012, 13(10), 4861-4866.
[7]
Davies, C.; Godwin, J.; Gray, R.; Clarke, M.; Cutter, D.; Darby, S. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: Patient-level meta-analysis of randomised trials. Lancet, 2011, 378(9793), 771-784.
[8]
Hudis, C.A. Trastuzumab-mechanism of action and use in clinical practice. N. Engl. J. Med., 2007, 357, 39-51.
[9]
Palmieri, C.; Patten, D.K.; Januszewski, A.; Zucchini, G.; Howell, S.J. Breast cancer: Current and future endocrine therapies. Mol. Cell. Endocrinol., 2014, 382(1), 695-723.
[10]
Gobbi, S.; Rampa, A.; Belluti, F.; Bisi, A. Antitumor alalkylphospholipids alter cell lipid metabolism. Anticancer. Agents Med. Chem., 2014, 14, 545-558.
[11]
Favia, A.D.; Nicolotti, O.; Stefanachi, A.; Leonetti, F.; Carotti, A. Computational methods for the design of potent aromatase inhibitors. Expert Opin. Drug Discov., 2013, 8(4), 395-409.
[12]
Hiscox, S.; Davies, E.L.; Barrett-Lee, P. Aromatase inhibitors in breast cancer. Maturitas, 2009, 63(4), 275-279.
[13]
To, S.Q.; Knower, K.C.; Cheunga, V.; Simpson, E.R.; Clynea, C.D. Transcriptional control of local estrogen formation by aromatase in the breast. J. Steroid Biochem. Mol. Biol., 2015, 145, 179-186.
[14]
Simpson, E.R.; Zhao, Y.; Agarwal, V.R.; Michael, M.D.; Bulun, S.E.; Hinshelwood, M.M.; Graham-Lorence, S.; Sun, T.; Fisher, C.R.; Qin, K.; Mendelson, C.R. Aromatase expression in health and disease. Recent Prog. Horm. Res., 1997, 52, 185-213.
[15]
Thompson, E.A.; Siiteri, P.K. Utilization of oxygen and reduced nicotinamide adenine dinucleotide phosphate by human placental microsomes during aromatization of androstenedione. J. Biol. Chem., 1974, 249(17), 5364-5372.
[16]
Chen, S.A.; Besman, M.J.; Sparkes, R.S.; Zollman, S.; Klisak, I.; Mohandas, T.; Hall, P.F.; Shively, J.E. Human aromatase: cDNA cloning, Southern blot analysis, and assignment of the gene to chromosome 15. DNA, 1988, 7(1), 27-38.
[17]
Ghosh, D.; Griswold, J.; Erman, M.; Pangborn, W. X-ray structure of human aromatase reveals an androgen-specific active site. J. Steroid Biochem. Mol. Biol., 2010, 118(4-5), 197-202.
[18]
Simpson, E.R.; Clyne, C.; Rubin, G.; Boon, W.C.; Robertson, K.; Britt, K.; Speed, C.; Jones, M. Aromatase-a brief overview. Annu. Rev. Physiol., 2002, 64, 93-127.
[19]
Osawa, Y.; Shibata, K.; Rohrer, D.; Weeks, C.; Duax, W.L. Reassignment of the absolute configuration of 19-substituted 19-hydroxysteroids and stereo mechanism of estrogen biosynthesis. J. Am. Chem. Soc., 1975, 1975(97), 4400-4402.
[20]
Murthy, N.; Rao, A.R.; Sastry, G.N. Aromatase inhibitors: A new paradigm in breast cancer treatment. Curr. Med. Chem. Anticancer Agents, 2004, 4, 523-534.
[21]
Wong, S.; Chen, J. The development, application and limitations of breast cancer cell lines to study tamoxifen and aromatase inhibitor resistance. J. Steroid Biochem. Mol. Biol., 2012, 131(3-5), 83-92.
[22]
Brueggemeier, R.W. Update on the use of aromatase inhibitors in breast cancer. Expert Opin. Pharmacother., 2006, 7(14), 1919-1930.
[23]
Dutta, U.; Pant, K. Understanding and management of male breast cancer: A critical review. Med. Oncol., 2008, 25, 294-298.
[24]
Seralini, G.; Moslemi, S. Aromatase inhibitors: Past, present and future. Mol. Cell. Endocrinol., 2001, 178, 117-131.
[25]
Cepa, M.; Tavares-da-Silva, E.; Correia-da-Silva, G.; Roleira, F.; Teixeira, N.A. Synthesis and biochemical studies of 17-substituted androst-3-enes and 3,4-epoxyandrostanes as aromatase inhibitors. Steroids, 2008, 73(14), 1409-1415.
[26]
Verma, S.K.; Thareja, S. Structure based comprehensive modelling, spatial fingerprints mapping and ADME screening of curcumin analogues as novel ALR2 inhibitors. PLoS One, 2017, 12, e0175318.
[27]
Varela, C.L.; Amaral, C.; Tavares da Silva, E.; Lopes, A.; Correia-da-Silva, G.; Carvalho, R.A.; Costa, S.C.P.; Roleira, F.M.F.; Teixeira, N. Exemestane metabolites: Synthesis, stereochemical elucidation, biochemical activity and anti-proliferative effects in a hormone dependent breast cancer cell line. Eur. J. Med. Chem., 2014, 87, 336-345.
[28]
Yadav, M.R.; Sabale, P.M.; Giridhar, R.; Zimmer, C.; Hartmann, R.W. Steroidal carbonitriles as potential aromatase inhibitors. Steroids, 2012, 77, 850-857.
[29]
Bansal, R.; Guleria, S.; Thota, S.; Bodhankar, S.L.; Patwardhan, M.R.; Zimmer, C.; Hartmann, R.W.; Harvey, A.L. Design, synthesis and evaluation of novel 16-imidazolyl substituted steroidal derivatives possessing potent diversified pharmacological properties. Steroids, 2012, 77(6), 621-629.
[30]
Amaral, C.; Varelac, C.; Azevedoa, M.; Tavares da Silva, E.; Roleirac, F.M.F.; Chend, S.; Correia-da-Silvaa, G.; Teixeiraa, N. Effects of steroidal aromatase inhibitors on sensitive and resistant breast cancer cells: Aromatase inhibition and autophagy. J. Steroid Biochem. Mol. Biol., 2013, 135, 51-59.
[31]
Bansal, R.; Thota, S.; Karkra, N.; Minu, M.; Zimmer, C.; Hartmann, R.W. Synthesis, Aromatase inhibitory activity of some new 16E-arylidenosteroids. Bioorg. Chem., 2012, 45, 3636-3640.
[32]
Varela, C.L.; Amaral, C.; Correia-da-Silva, G.; Carvalho, R.A.; Teixeira, N.A.; Costa, S.C.; Roleira, F.M.F.; Tavares-da-Silva, E.J. Design, synthesis and biochemical studies of new 7α-allylandrostanes as aromatase inhibitors. Steroids, 2013, 78(7), 662-669.
[33]
Verma, S.K.; Thareja, S. Molecular docking assisted 3D-QSAR study of benzylidene-2, 4-thiazolidinedione derivatives as PTP-1B inhibitors for the management of Type-2 diabetes mellitus. RSC Advances, 2016, 6, 33857-33867.
[34]
Verma, S.K.; Rajpoot, T.; Gautam, M.K.; Jain, A.K.; Thareja, S. Design of novel biphenyl-2-thioxothiazolidin-4-one derivatives as potential protein tyrosine phosphatase (PTP)-1B inhibitors using molecular docking study. Lett. Drug Des. Discov., 2016, 13(4), 295-300.
[35]
Protein data bank. http://www.rcsb.org/pdb/explore/explore.do? structureId=3S79 (Accessed April 01, 2018).
[36]
Verma, S.K.; Sharma, S.K.; Thareja, S. Docking study of novel pyrrolidine derivatives as potential dipeptidyl peptidase-IV (DPP-IV) inhibitors. Lett. Drug Des. Discov., 2015, 12, 284-291.
[37]
Verma, S.K.; Thareja, S. Formylchromone derivatives as novel and selective PTP-1B inhibitors: A drug design aspect using molecular docking-based self-organizing molecular field analysis. Med. Chem. Res., 2016, 25(7), 1433-1467.
[38]
Robinson, D.D.; Winn, P.J.; Lyne, P.D.; Richards, W.G. Self-organizing molecular field analysis: A tool for structure-activity studies. J. Med. Chem., 1999, 42(4), 573-583.
[39]
Thareja, S.; Verma, S.K.; Haksar, D.; Bhardwaj, T.R.; Kumar, M. Discovery of novel cinnamylidene-thiazolidinedione derivatives as PTP-1B inhibitors for the management of type 2 diabetes. RSC Advances, 2016, 6(110), 108928-108940.
[40]
Thareja, S.; Rajpoot, T.; Verma, S.K. Generation of comparative pharmacophoric model for steroidal 5α-reductase I and II inhibitors: A 3D-QSAR study on 6-azasteroids. Steroids, 2015, 95, 96-103.
[41]
Ghosh, D.; Griswold, J.; Erman, M.; Pangborn, W. Structural basis for androgen specificity and oestrogen synthesis in human aromatase. Nature, 2009, 457(7226), 219-223.
[42]
Golbraikh, A.; Tropsha, A. Beware of q2! J. Mol. Graph. Model., 2002, 20(4), 269-276.


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Article Details

VOLUME: 16
ISSUE: 7
Year: 2019
Page: [808 - 817]
Pages: 10
DOI: 10.2174/1570180815666181010101024
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