Molecular Modeling, Docking and ADMET of Dimethylthiohydantoin Derivatives for Prostate Cancer Treatment


In silico technique was applied to screen potential of 16 compounds of 5,5-dimethylthiohydantoin derivatives as androgen antagonist. The 3D structure of the protein was obtained from PDB database. Docking analysis of the compounds was performed using hex docking. Molecular modeling analysis exhibits relatively low LUMO-HOMO energy gap of the studied molecules, indicating that it would be kinetically stable. None of the compounds violated Lipinski’s parameters, making them potentially promising agents for biological activities. The title compounds exhibited the lowest docking energy of protein-ligand complex. Finally, the results indicate that these compounds are potentially as an androgen antagonist, and expected to be effective in prostate cancer treatment.

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Lotfy, K. (2015) Molecular Modeling, Docking and ADMET of Dimethylthiohydantoin Derivatives for Prostate Cancer Treatment. Journal of Biophysical Chemistry, 6, 91-117. doi: 10.4236/jbpc.2015.64010.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Green, D.R. and Kroemer, G. (2004) The Pathophysiology of Mitochondrial Cell Death. Science, 305, 626-629.
[2] Hanahan, D. and Folkman, J. (1996) Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis. Cell, 86, 353-364.
[3] Hartwell, L.H. and Kastan, M.B. (1994) Cell Cycle Control and Cancer. Science, 266, 1821-1828.
[4] Risau, W. (1997) Mechanisms of Angiogenesis. Nature, 386, 671-674.
[5] Heidenreich, A., Bellmunt, J., Bolla, M., Joniau, S., Mason, M., Matveev, V., Mottet, N., Schmid, H.P., van der, K.T., Wiegel, T. and Zattoni, F. (2011) Guía de La EAU sobre el cáncer de próstata. Parte I: Cribado, diagnóstico y tratamiento del áncer clínicamente localizado. Actas Urológicas Españolas, 35, 501-514.
[6] Culig, Z., Klocker, H., Bartsch, G. and Hobisch, A. (2002) Androgen Receptors in Prostate Cancer. Endocrine Related Cancer, 9, 155-170.
[7] Culig, Z., Klocker, H., Bartsch, G. and Hobisch, A. (2001) Androgen Receptor Mutations in Carcinoma of the Prostate. American Journal of Pharmaco-Genomics, 1, 241-249.
[8] Eder, I.E., Culig, Z., Putz, T., Nessler-Menardi, C., Bartsch, G. and Klocker, H. (2001) Molecular Biology of the Androgen Receptor: From Molecular Understanding to the Clinic. European Urology, 40, 241-251.
[9] Huggins, C. and Hodges, C.V. (1972) Studies on Prostatic Cancer: I. The Effect of Castration, of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the Prostate. CA: A Cancer Journal for Clinicians, 22, 232-240.
[10] Wang, D. and Tindall, D.J. (2011) Androgen Action during Prostate Carcinogenesis. Methods in Molecular Biology, 776, 25-44.
[11] Green, S.M., Mostaghel, E.A. and Nelson, P.S. (2012) Androgen Action and Metabolism in Prostate Cancer. Molecular and Cellular Endocrinology, 360, 3-13.
[12] McPhaul, M.J. (2002) Androgen Receptor Mutations and Androgen Insensitivity. Molecular and Cellular Endocrinology, 198, 61-67.
[13] Yeh, S., Tsai, M.Y., Xu, Q., Mu, X.M., Lardy, H., Huang, K.E., Lin, H., Yeh, S.D., Altuwaijri, S., Zhou, X., Xing, L., Boyce, B., Hung, M., Zhang, S., Gan, L. and Chang, C. (2002) Generation and Characterization of Androgen Receptor Knockout (ARKO) Mice: An in Vivo Model for the Study of Androgen Functions in Selective Tissues. Proceedings of the National Academy of Sciences of the United States of America, 99, 13498-13503.
[14] Hirawat, S., Budman, D.R. and Kreis, W. (2003) The Androgen Receptor: Structure, Mutations, and Antiandrogens. Cancer Investigation, 21, 400-417.
[15] Heinlein, C.A. and Chang, C. (2004) Androgen Receptor in Prostate Cancer. Endocrine Reviews, 25, 276-308.
[16] Bevan, C.L. (2005) Androgen Receptor in Prostate Cancer: Cause or Cure? Trends in Endocrinology & Metabolism, 16, 395-397.
[17] He, Y., Yin, D., Perera, M., Kirkovsky, L., Stourman, N., Li, W., Dalton, J. and Miller, D. (2002) Novel Nonsteroidal Ligands with High Binding Affinity and Potent Functional Activity for the Androgen Receptor. European Journal of Medicinal Chemistry, 37, 619-634.
[18] Dalton, J.T., Mukherjee, A., Zhu, Z., Kirkovsky, L. and Miller, D.D. (1998) Discovery of Nonsteroidal Androgens. Biochemical and Biophysical Research Communications, 244, 1-4.
[19] Feldman, B.J. and Feldman, D. (2001) The Development of Androgen-Independent Prostate Cancer. Nature Reviews Cancer, 1, 34-45.
[20] Chen, Y., Sawyers, C.L. and Scher, H.I. (2008) Targeting the Androgen Receptor Pathway in Prostate Cancer. Current Opinion in Pharmacology, 8, 440-448.
[21] Taplin, M.E. (2008) Androgen Receptor: Role and Novel Therapeutic Prospects in Prostate Cancer. Expert Review of Anticancer Therapy, 8, 1495-1508.
[22] Yap, T.A., Zivi, A., Omlin, A. and de Bono, J.S. (2011) The Changing Therapeutic Landscape of Castration-Resistant Prostate Cancer. Nature Reviews Clinical Oncology, 8, 597-610.
[23] Courtney, K.D. and Taplin, M.E. (2012) The Evolving Paradigm of Second-Line Hormonal Therapy Options for Castration-Resistant Prostate Cancer. Current Opinion in Oncology, 24, 272-277.
[24] Isbarn, H., Boccon-Gibod, L., Carroll, P.R., Montorsi, F., Schulman, C., Smith, M.R., Sternberg, C.N. and Studer, U.E. (2009) Androgen Deprivation Therapy for the Treatment of Prostate Cancer: Consider Both Benefits and Risks. European Urology, 55, 62-75.
[25] Wirth, M.P., Hakenberg, O.W. and Froehner, M. (2007) Antiandrogens in the Treatment of Prostate Cancer. European Urology, 51, 306-313.
[26] See, W.A., Wirth, M.P., McLeod, D.G., Iversen, P., Klimberg, I., Gleason, D., Chodak, G., Montie, J., Tyrrell, C., Wallace, D.M.A., Delaere, K.P.J., Vaage, S., Tammela, T.L.J., Lukkarinen, O., Persson, B.-E., Carrol, K. and Kolvenbag, G.J.C.M. (2002) Bicalutamide as Immediate Therapy Either Alone or as Adjuvant to Standard Care of Patients with Localized or Locally Advanced Prostate Cancer: First Analysis of the Early Prostate Cancer Program. The Journal of Urology, 168, 429-435.
[27] Akaza, H., Yamaguchi, A., Matsuda, T., Igawa, M., Kumon, H., Soeda, A., Arai, Y., Usami, M., Naito, S., Kanetake, H. and Ohashi, Y. (2004) Superior Anti-tumor Efficacy of Bicalutamide 80 mg in Combination with a Luteinizing Hormone-Releasing Hormone (LHRH) Agonist versus LHRH Agonist Monotherapy as First-Line Treatment for Advanced Prostate Cancer: Interim Results of a Randomized Study in Japanese Patients. Japanese Journal of Clinical Oncology, 34, 20-28.
[28] Wirth, M.P., See, W.A., McLeod, D.G., Iversen, P., Morris, T. and Carroll, K. (2004) Bicalutamide 150 mg in Addition to Standard Care in Patients with Localized or Locally Advanced Prostate Cancer: Results from the Second Analysis of the Early Prostate Cancer Program at Median Follow-Up of 5.4 Years. The Journal of Urology, 172, 1865-1870.
[29] Iversen, P., Johansson, J.E., Lodding, P., Lukkarinen, O., Lundmo, P., Klarskov, P., Tammela, T.L., Tasdemir, I., Morris, T. and Carroll, K. (2004) Bicalutamide (150 mg) versus Placebo as Immediate Therapy Alone or as Adjuvant to Therapy with Curative Intent for Early Nonmetastatic Prostate Cancer: 5.3-Year Median Follow-Up from the Scandinavian Prostate Cancer Group Study Number 6. The Journal of Urology, 172, 1871-1876.
[30] Isurugi, K., Fukutani, K., Ishida, H. and Hosoi, Y. (1980) Endocrine Effects of Cyproterone Acetate in Patients with Prostatic Cancer. The Journal of Urology, 123, 180-183.
[31] Kennealey, G.T. and Furr, B.J. (1996) Use of the Nonsteroidal Anti-Androgen Casodex in Advanced Prostatic Carcinoma. Urologic Clinics of North America, 18, 99-110.
[32] Blackledge, G.R. (1996) Clinical Progress with a New Antiandrogen, Casodex (Bicalutamide). European Urology, 2, 96-104.
[33] Tyrrell, C.J., Altwein, J.E., Klippel, F., Varenhorst, E., Lunglmayr, G., Boccardo, F., Holdaway, I.M., Haefliger, J.M. and Jordaan, J.P. (1991) A Multicenter Randomized Trial Comparing the Luteinizing Hormone-Releasing Hormone Analogue Goserelin Acetate Alone and with Flutamide in the Treatment of Advanced Prostate Cancer. The International Prostate Cancer Study Group. The Journal of Urology, 146, 1321-1326.
[34] Eisenberger, M.A., Blumenstein, B.A., Crawford, E.D., Miller, G., McLeod, D.G., Loehrer, P.J., Wilding, G., Sears, K., Culkin Jr., D.J., Thompson, I.M., Bueschen, A.J. and Lowe, B.A. (1998) Bilateral Orchiectomy with or without Flutamide for Metastatic Prostate Cancer. New England Journal of Medicine, 339, 1036-1042.
[35] Wirth, M.P. and Froschermaier, S.E. (1997) The Antiandrogen Withdrawal Syndrome. Urological Research, 25, 67-71.
[36] Kemppainen, J.A. and Wilson, E.M. (1996) Agonist and Antagonist Activities of Hydroxyflutamide and Casodex Relate to Androgen Receptor Stabilization. Urology, 48, 157-163.
[37] Tachibana, K., Imaoka, I., Shiraishi, T., Yoshino, H., Nakamura, M., Ohta, M., Kawata, H., Taniguchi, K., Ishikura, N., Tsunenari, T., Saito, H., Nagamuta, M., Nakagawa, T., Takanashi, K., Onuma, E. and Sato, H. (2008) Discovery of an Orally-Active Nonsteroidal Androgen Receptor Pure Antagonist and the Structure-Activity Relationships of Its Derivatives. Chemical & Pharmaceutical Bulletin, 56, 1555-1561.
[38] Yoshino, H., Sato, H., Tachibana, K., Shiraishi, T., Nakamura, M., Ohta, M., Ishikura, N., Nagamuta, M., Onuma, E., Nakagawa, T., Arai, S., Ahn, K.H., Jung, K.Y. and Kawata, H. (2010) Structure-Activity Relationships of Bioisosteric Replacement of the Carboxylic Acid in Novel Androgen Receptor Pure Antagonists. Bioorganic & Medicinal Chemistry, 18, 3159-3168.
[39] Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., Petersson, G.A., Nakatsuji, H., Caricato, M., Li, X., Hratchian, H.P., Izmaylov, A.F., Bloino, J., Zheng, G., Sonnenberg, J.L., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Vreven, T., Montgomery Jr., J.A., Peralta, J.E., Ogliaro, F., Bearpark, M., Heyd, J.J., Brothers, E., Kudin, K.N., Staroverov, V.N., Kobayashi, R., Normand, J., Raghavachari, K., Rendell, A., Burant, J.C., Iyengar, S.S., Tomasi, J., Cossi, M., Rega, N., Millam, J.M., Klene, M., Knox, J.E., Cross, J.B., Bakken, V., Adamo, C., Jaramillo, J., Gomperts, R., Stratmann, R.E., Yazyev, O., Austin, A.J., Cammi, R., Pomelli, C., Ochterski, J.W., Martin, R.L., Morokuma, K., Zakrzewski, V.G., Voth, G.A., Salvador, P., Dannenberg, J.J., Dapprich, S., Daniels, A.D., Farkas, O., Foresman, J.B., Ortiz, J.V., Cioslowski, J. and Fox, D.J. (2009) Gaussian 09, Revision A. Gaussian, Inc., Wallingford.
[40] Dennington, R., Keith, T. and Millam, J. (2007) Gauss View, Version 4.1.2. Semichem Inc., Shawnee Mission.
[41] Lipinski, C.A., Lombardo, F., Dominy, B.W. and Feeney, P.J. (1997) Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Advanced Drug Delivery Reviews, 64, 4-17.
[42] Molinspiration Cheminformatics (Homepage on the Internet). Nova Ulica, SK-900 26 Slovensky Grob, Slovak Republic.
[43] Molsoft Offers Software Tools and Services in Lead Discovery, Modeling, Cheminformatics, Bioinformatics.
[44] Chen, G., Zheng, S., Luo, X., Shen, J., Zhu, W., Liu, H., Gui, C., Zhang, J., Zheng, M., Puah, C.M., Chen, K. and Jiang, H. ( 2005) Focused Combinatorial Library Design Based on Structural Diversity, Druglikeness and Binding Affinity Score. Journal of Combinatorial Chemistry, 7, 398-406.
[46] Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N. and Bourne, P.E. (2000) The Protein Data Bank. Nucleic Acids Research, 28, 235-242.
[47] Laskowski, R.A., MacArthur, M.W., Moss, D.S. and Thornton, J.M. (1993) PROCHECK: A Program to Check the Stereochemical Quality of Protein Structures. Journal of Applied Crystallography, 26, 283-291.
[48] Ritchie, W.D. and Kemp, G.J.L. (2000) Protein Docking Using Spherical Polar Fourier Correlations. Proteins: Structure, Function, and Genetics, 39, 178-194.
[49] Ritchie, W.D. (2003) Evaluation of Protein Docking Predictions Using Hex 3.1 in CAPRI Rounds 1 and 2. Proteins: Structure, Function, and Bioinformatics, 52, 98-106.
[50] Delano, W.L. (2002) The PyMOL Molecular Graphics System. De Lano Scientific, San Carlos.
[51] Laskowski, R.A. and Swindells, M.B. (2011) LigPlot+: Multiple Ligand-Protein Interaction Diagrams for Drug Discovery. Journal of Chemical Information and Modeling, 51, 2778-2786.
[52] Zhao, Y.H., Abraham, M.H., Le, J., Hersey, A., Luscombe, C.N., Beck, G. and Sherborne, B. (2002) Rate-Limited Steps of Human Oral Absorption and QSAR Studies. Pharmaceutical Research, 19, 1446-1457.
[53] Cheng, F., Li, W., Zhou, Y., Shen, J., Wu, Z., Liu, G., Lee, P. and Tang, Y. (2012) admetSAR: A Comprehensive Source and Free Tool for Assessment of Chemical ADMET Properties. Journal of Chemical Information and Modeling, 52, 3099-3105.
[54] Awad, M.K., Khairau, K.S. and Diab, M.A. (1994) Theoretical Investigations of the Stability of Degradation Products of Polystyrene and Poly(4-vinylpyridine). Polymer Degradation and Stability, 46, 165-170.
[55] Ghanty, T.K. and Ghosh, S.K. (1996) A Density Functional Approach to Hardness, Polarizability, and Valency of Molecules in Chemical Reactions. The Journal of Physical Chemistry, 100, 12295-12298.
[56] Parr, R.G., Szentpaly, L.V. and Liu, S.J. (1999) Electrophilicity Index. Journal of the American Chemical Society, 121, 1922-1924.
[57] Lipinski, C.A., Lombardo, F., Dominy, B.W. and Feeney, P. (2012) Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Advanced Drug Delivery Reviews, 64, 4-17.
[58] Veber, D.F., Johnson, S.R., Cheng, H.Y., Smith, B.R., Ward, K.W. and Kapple, K.D. (2002) Molecular Properties That Influence the Oral Bioavailability of Drug Candidates. Journal of Medicinal Chemistry, 45, 2615-2623.
[59] Ertl, P., Rohde, B. and Selzer, P. (2000) Fast Calculation of Molecular Polar Surface Area as a Sum of Fragment-Based Contributions and Its Application to the Prediction of Drug Transport Properties. Journal of Medicinal Chemistry, 43, 3714-3717.
[60] Pervez, A., Meshram, J., Tiwari, V., Sheik, J., Dongre, R., Youssoufi, M.H., et al. (2010) Pharmacophores Modeling in Terms of Prediction of Theoretical Physico-Chemical Properties and Verification by Experimental Correlations of Novel Coumarin Derivatives Produced via Betti’s Protocol. European Journal of Medicinal Chemistry, 45, 4370-4378.
[61] Clark, D.E. (1999) Rapid Calculation of Polar Molecular Surface Area and Its Application to the Prediction of Transport Phenomena. 2. Prediction of Blood-Brain Barrier Penetration. Journal of Pharmaceutical Sciences, 88, 815-821.
[62] Lalitha, P. and Sivakamasundari, S. (2010) Calculation of Molecular Lipophilicity and Druglikeness for Few Heterocycles. Oriental Journal of Chemistry, 26, 135-141.
[63] Verma, A. (2012) Lead Finding from Phyllanthus debelis with Hepatoprotective Potentials. Asian Pacific Journal of Tropical Biomedicine, 2, S1735-S1737.
[64] Lagunin, A., Stepanchikova, A., Filimonov, D. and Poroikov, V. (2000) PASS: Prediction of Activity Spectra for Biologically Active Substances. Bioinformatics, 16, 747-748.

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