In Silico Screening, Design and Synthesis of Novel Inhibitors against Histone Deacetylase (HDAC)

Abstract

Finding a new treatment for cancer is one of the most interested fields for pharmaceutical research worldwide. As a member of HDAC class I, histone deacetylase 2 (HDAC2) appears to be an important druggable target. Today, computer-aided drug design is increasingly used in the drug discovery and development processes. In this study, computational methods, including Quantitative Structure-Activity Relationship and Molecular Docking approaches, have been explored for virtual screening as well as rational design of potential inhibitors of HDAC enzymes. The main results included the identification of 3 novel structure scaffolds, which had never been studied in anti-HDAC or anticancer activities. In particular, ibandronic acid showed very good half-maximal inhibitory concentration against HDAC extracted from MCF-7 cell line (IC₅₀ of 15 µM) and citotoxicity of < 50 µM against three cancer cell lines (MCF-7, LNCaP, and SK-LU-1). On the other hand, six novel series of HDAC2 inhibitors were rationally designed using molecular descriptors derived from ISIDA fragmentor methodology. A series of novel hydroxamates incorporating oxoindoline aromatic system was synthesized and evaluated in the inhibitory activity against HDAC2 enzyme. The results showed that three synthesized compounds (4a-c) exhibited very good inhibitory potency, with IC₅₀ ranged from 1.70-6.24 µM; notably, compound 4a displayed similar potency to that of Vorinostat (SAHA), a commercial drug currently used in the management of cutaneous T cell lymphoma. Physicochemical and molecular simulation profiling assays suggested that this compound was drug-like and suitable for further study towards developing it into new anti-cancer drug.

Keywords

QSAR, Molecualr Docking, anticancer, rational drug design, HDAC.

References

C. Avendaño, J.C. Menéndez. Chapter 13 - Drug Targeting in Anticancer Chemotherapy. In: Menéndez CAC (ed) Medicinal Chemistry of Anticancer Drugs (Second Edition). Elsevier, Boston, (2015) 595.
[2] S.Y. Roth, et al., Histone acetyltransferase. Annual review of biochemistry, 70 (2001) 81.
[3] P. Bertrand, Inside HDAC with HDAC inhibitors. European journal of medicinal chemistry 45 (2010) 116.
[4] M. Claude, Histone deacetylase inhibitors. European journal of medicinal chemistry 40 (2005) 1.
[5] L. Zhang, et al., Strategies in developing promising histone deacetylase inhibitors. Medicinal Research Reviews 30 (2010) 585.
[6] C. Nicola, et al., Chapter One - Recent Advances in Cancer Therapeutics. In: Lawton G, Witty DR (eds) Progress in Medicinal Chemistry, vol 54. Elsevier, (2015) 1.
[7] H. Pham-The, et al., Quantitative structure–activity relationship analysis and virtual screening studies for identifying HDAC2 inhibitors from known HDAC bioactive chemical libraries. SAR and QSAR in Environmental Research 28 (2017) 199.
[8] H. Pham-The, H. Le-Thi-Thu. Integrating Structure and Ligand-Based Approaches for Modelling the Histone Deacetylase inhibition activity of Hydroxamic Acid derivatives. Asian Journal of Pharmaceutical and Clinical Research 11 (2018) 199.
[9] D. Kirschner, et al., Method for detecting the 3-hydroxymyristic acid component of the endotoxins of gram-negative bacteria in compost samples. American Industrial Hygiene Association 46 (1985) 741.
[10] F. Bauss. Ibandronate: the first once-monthly oral bisphosphonate for treatment of postmenopausal osteoporosis. Therapeutics and Clinical Risk Management 2 (2006) 3
[11] H. B. Sittig, Pathogenesis and bisphosphonate treatment of skeletal events and bone pain in metastatic cancer: focus on ibandronate. Onkologie 35 (2012) 380.
[12] L. Y. McGirt, et al. Successful treatment of recalcitrant chronic idiopathic urticaria with sulfasalazine. Archives of Dermatology 142 (2006) 1337
[13] N. Weidner, et al. Sulfasalazine in treatment of collagenous colitis. Case report and review of the literature. American Journal of Medicine 77 (1984) 162.
[14] A. Varnek, et al., ISIDA - Platform for Virtual Screening Based on Fragment and Pharmacophoric Descriptors. Current Computer-Aided Drug Design 4 (2008) 191.
[15] V. Consonni and D. Ballabio, Comments on the definition of the Q2 parameter for QSAR validation. Journal of Chemical Information and Modeling 49 (2009) 1669.
[16] N.T.T. Hoài and P.T.T.Q. Chiến, Thuật giải di truyền và ứng dụng. Tuyển tập Báo cáo Hội nghị Sinh viên nghiên cứu khoa học lần thứ 6 (2008) 266.