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