Trends in Bioinformatics1994-79412077-2254Asian Network for Scientific Information10.3923/tb.2013.25.44SangeethaS. RanjithaS. MuruganK. KumarG. Ramesh 2201362Histone deacetylases 1 and 3 (HDAC1 and HDAC3) enzyme chromatin remodeling
and gene transcription altering activities are implicated in tumor behavior
and progression. Their inhibitors promising pre-clinical model therapeutic efficacy
makes them likely anti-cancer targets for breast cancer therapeutic intervention.
In this study, both natural and synthetic Histone Deacetylase Inhibitors (HDACi)
were screened using in silico docking, molecular descriptors and pharmacophore
models to design new molecules with potential HDAC1 and HDAC3 selectivity and
inhibitory activity. Three dimensional (3D) homology models of HDAC1 and HDAC3
were built based on the crystal structure of human Histone deacetylase 2 (HDAC2).
Lead optimization by docking several natural and synthetic compounds were carried
out and compared. There are several natural HDACi available and curcumin was
found to be best docked to HDAC1 and HDAC3. Through Virtual Screening (VS) top-scored
compound curcumin was identified but it shows poor drug likeness property. To
overcome this problem pharmacophore modeling of the curcumin based on virtual
screening of (1E, 4E)-1,5-bis (3, 4-dimethoxyphenyl) penta-1, 4- dien-3-one
was studied. This study was found to be best docked to HDAC1 and HDAC3 with
highest binding energies -10.20 and -10.27 kcal/mol, respectively and interacts
with active site of catalytic Zn2+ trihedrally coordinates to the
side chains of amino acids. Curcumin analogue was predicted as a potential lead
drug-like molecule that selectively inhibits HDAC1 and HDAC3 that may prevent
the progression and pathogenesis of breast cancer.]]>Binkowski, T.A., S. Naghibzadeh and J. Liang,20033133523355Friedrich, A., R. Ripp, N. Garnier, E. Bettler, G. Deleage, O. Poch and L. Moulinier,20072007Chou, C.W., M.S. Wu, W.C. Huang and C.C. Chen,20112011Lipinski, C.A., F. Lombardo, B.W. Dominy and P.J. Feeney,200146326Seeliger, D. and B.L. de Groot,201024417422Wishart, D.S., C. Knox, A.C. Guo, D. Cheng and S. Shrivastava et al.,200836D901D906Duong, V., C. Bret, L. Altucci, A. Mai and C. Duraffourd et al.,2008619081919Dworkin, A.M., T.H.M. Huang and A.E. Toland,200919165171Ertl, P.,20122054365442Morris, G.M., D.S. Goodsell, R.S. Halliday, R. Huey, W.E. Hart, R.K. Belew and A.J. Olson,19981916391662Reuter, S., S.C. Gupta, B. Park, A. Goel and B.B. Aggarwal,2011693108Jemal, A., F. Bray, M.M. Center, J. Ferlay, E. Ward and D. Forman,2011616990Seiler, K.P., G.A. George, M.P. Happ, N.E. Bodycombe and H.A. Carrinski et al.,200836D351D359Krusche, C.A., P. Wulfing, C. Kersting, A. Vloet and W. Bocker et al.,2005901523Laskowski, R.A., M.W. MacArthur, D.S. Moss and J.M. Thornton,199326283291Geer, L.Y., A. Marchler-Bauer, R.C. Geer, L. Han and J. He et al.,201038D492D496Lustberg, M.B. and B. Ramaswamy,201133443Paramasivan, M., G. Sankaran, N. Sethuraman, D.S. Devadoss, S. Thangavelu and M. Gangatharan,2011Helicobacter pylori J 99 and predicting an interruption in interaction by Vigna radiata Defensins.]]>5410415Mariotto, A.B., K.R. Yabroff, Y. Shao, E.J. Feuer and M.L. Brown,2011103117128Noureen, N., S. Kalsoom and H. Rashid,2010939233931Osterberg, T. and U. Norinder,200112327337Oyama, T., Y. Yasui and T. Tanaka,20095198208Phosrithong, N. and J. Ungwitayatorn,201019817835Li, Q., T. Cheng, Y. Wang and S.H. Bryant,20101510521057Alteri, R., P. Bandi, L. Brinton, C. Casares and V. Cokkinides et al.,20112011Chakraborti, S., L. Das, N. Kapoor, A. Das and V. Dwivedi et al.,20115461836196Subha, K. and G.R. Kumar,20083218222Tambunan, U.S.F. and E.K. Wulandari,20102010Yang, W.M., S.C. Tsai, Y.D. Wen, G. Fejer and E. Seto,200227794479454Tsai, Y.M., C.F. Chien, L.C. Lin and T.H. Tsai,2011416331338Akram, M., Shahab-Uddin, A. Ahmed, K. Usmanghani, A. Hannan, E. Mohiuddin and M. Asif,2010Curcuma longa and curcumin: A review article.]]>556570Izawa, M., O. Takekawa, T. Arie, T. Teraoka, M. Yoshida, M. Kimura and T. Kamakura,2009Magnaporthe oryzae.]]>55489498