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doi.org/10.1016/j.bmcl.2006.10.048
51. Tang H, Wang XS, Huang XP, Roth BL, Butler KV, Kozikowski AP, Jung M, Tropsha A
(2009) Novel inhibitors of human histone deacetylase (HDAC) identified by QSAR modeling
of known inhibitors, virtual screening, and experimental validation. J Chem Inf Model 49
(2):461–476. https://doi.org/10.1021/ci800366f
52. Park H, Kim S, Kim YE, Lim SJ (2010) A structure-based virtual screening approach toward
the discovery of histone deacetylase inhibitors: identification of promising zinc-chelating
groups. ChemMedChem 5(4):591–597. https://doi.org/10.1002/cmdc.200900500
53. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational
approaches to estimate solubility and permeability in drug discovery and development settings
(Reprinted from Advanced Drug Delivery Reviews, vol 23, pp 3–25, 1997). Adv Drug Deliver
Rev 46(1–3):3–26. https://doi.org/10.1016/S0169-409x(00)00129-0
54. Kannan S, Melesina J, Hauser AT, Chakrabarti A, Heimburg T, Schmidtkunz K, Walter A,
Marek M, Pierce RJ, Romier C, Jung M, Sippl W (2014) Discovery of inhibitors of
Schistosoma mansoni HDAC8 by combining homology modeling, virtual screening, and
in vitro validation. J Chem Inf Model 54(10):3005–3019. https://doi.org/10.1021/ci5004653
55. Marek M, Kannan S, Hauser AT, Moraes Mourao M, Caby S, Cura V, Stolfa DA,
Schmidtkunz K, Lancelot J, Andrade L, Renaud JP, Oliveira G, Sippl W, Jung M,
Cavarelli J, Pierce RJ, Romier C (2013) Structural basis for the inhibition of histone
deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni.
PLoS Pathog 9(9):e1003645. https://doi.org/10.1371/journal.ppat.1003645
56. Heimburg T, Chakrabarti A, Lancelot J, Marek M, Melesina J, Hauser AT, Shaik TB,
Duclaud S, Robaa D, Erdmann F, Schmidt M, Romier C, Pierce RJ, Jung M, Sippl W
(2016) Structure-based design and synthesis of novel inhibitors targeting HDAC8 from
Schistosoma mansoni for the treatment of schistosomiasis. J Med Chem 59(6):2423–2435.
https://doi.org/10.1021/acs.jmedchem.5b01478
57. Heimburg T, Kolbinger FR, Zeyen P, Ghazy E, Herp D, Schmidtkunz K, Melesina J, Shaik
TB, Erdmann F, Schmidt M, Romier C, Robaa D, Witt O, Oehme I, Jung M, Sippl W (2017)
Structure-based design and biological characterization of selective histone deacetylase
8 (HDAC8) inhibitors with anti-neuroblastoma activity. J Med Chem 60(24):10188–10204.
https://doi.org/10.1021/acs.jmedchem.7b01447
58. Butler KV, Kalin J, Brochier C, Vistoli G, Langley B, Kozikowski AP (2010) Rational design
and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A. J Am
Chem Soc 132(31):10842–10846. https://doi.org/10.1021/ja102758v
59. Micelli C, Rastelli G (2015) Histone deacetylases: structural determinants of inhibitor selectivity. Drug Discov Today 20(6):718–735. https://doi.org/10.1016/j.drudis.2015.01.007
60. De Vreese R, D'Hooghe M (2017) Synthesis and applications of benzohydroxamic acid-based
histone deacetylase inhibitors. Eur J Med Chem 135:174–195. https://doi.org/10.1016/j.
ejmech.2017.04.013
61. Davenport AM, Huber FM, Hoelz A (2014) Structural and functional analysis of human
SIRT1. J Mol Biol 426(3):526–541. https://doi.org/10.1016/j.jmb.2013.10.009
62. Zhao X, Allison D, Condon B, Zhang FY, Gheyi T, Zhang AP, Ashok S, Russell M,
MacEwan I, Qian YW, Jamison JA, Luz JG (2013) The 2.5 angstrom crystal structure of the
SIRT1 catalytic domain bound to nicotinamide adenine dinucleotide (NAD(+)) and an indole
(EX527 analogue) reveals a novel mechanism of histone deacetylase inhibition. J Med Chem
56(3):963–969. https://doi.org/10.1021/jm301431y
63. Finnin MS, Donigian JR, Pavletich NP (2001) Structure of the histone deacetylase SIRT2. Nat
Struct Biol 8(7):621–625. https://doi.org/10.1038/89668
64. Moniot S, Schutkowski M, Steegborn C (2013) Crystal structure analysis of human Sirt2
and its ADP-ribose complex. J Struct Biol 182(2):136–143. https://doi.org/10.1016/j.jsb.2013.
02.012
Structure-Based Design of Epigenetic Inhibitors
479
doi.org/10.1016/j.bmcl.2006.10.048
51. Tang H, Wang XS, Huang XP, Roth BL, Butler KV, Kozikowski AP, Jung M, Tropsha A
(2009) Novel inhibitors of human histone deacetylase (HDAC) identified by QSAR modeling
of known inhibitors, virtual screening, and experimental validation. J Chem Inf Model 49
(2):461–476. https://doi.org/10.1021/ci800366f
52. Park H, Kim S, Kim YE, Lim SJ (2010) A structure-based virtual screening approach toward
the discovery of histone deacetylase inhibitors: identification of promising zinc-chelating
groups. ChemMedChem 5(4):591–597. https://doi.org/10.1002/cmdc.200900500
53. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational
approaches to estimate solubility and permeability in drug discovery and development settings
(Reprinted from Advanced Drug Delivery Reviews, vol 23, pp 3–25, 1997). Adv Drug Deliver
Rev 46(1–3):3–26. https://doi.org/10.1016/S0169-409x(00)00129-0
54. Kannan S, Melesina J, Hauser AT, Chakrabarti A, Heimburg T, Schmidtkunz K, Walter A,
Marek M, Pierce RJ, Romier C, Jung M, Sippl W (2014) Discovery of inhibitors of
Schistosoma mansoni HDAC8 by combining homology modeling, virtual screening, and
in vitro validation. J Chem Inf Model 54(10):3005–3019. https://doi.org/10.1021/ci5004653
55. Marek M, Kannan S, Hauser AT, Moraes Mourao M, Caby S, Cura V, Stolfa DA,
Schmidtkunz K, Lancelot J, Andrade L, Renaud JP, Oliveira G, Sippl W, Jung M,
Cavarelli J, Pierce RJ, Romier C (2013) Structural basis for the inhibition of histone
deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni.
PLoS Pathog 9(9):e1003645. https://doi.org/10.1371/journal.ppat.1003645
56. Heimburg T, Chakrabarti A, Lancelot J, Marek M, Melesina J, Hauser AT, Shaik TB,
Duclaud S, Robaa D, Erdmann F, Schmidt M, Romier C, Pierce RJ, Jung M, Sippl W
(2016) Structure-based design and synthesis of novel inhibitors targeting HDAC8 from
Schistosoma mansoni for the treatment of schistosomiasis. J Med Chem 59(6):2423–2435.
https://doi.org/10.1021/acs.jmedchem.5b01478
57. Heimburg T, Kolbinger FR, Zeyen P, Ghazy E, Herp D, Schmidtkunz K, Melesina J, Shaik
TB, Erdmann F, Schmidt M, Romier C, Robaa D, Witt O, Oehme I, Jung M, Sippl W (2017)
Structure-based design and biological characterization of selective histone deacetylase
8 (HDAC8) inhibitors with anti-neuroblastoma activity. J Med Chem 60(24):10188–10204.
https://doi.org/10.1021/acs.jmedchem.7b01447
58. Butler KV, Kalin J, Brochier C, Vistoli G, Langley B, Kozikowski AP (2010) Rational design
and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A. J Am
Chem Soc 132(31):10842–10846. https://doi.org/10.1021/ja102758v
59. Micelli C, Rastelli G (2015) Histone deacetylases: structural determinants of inhibitor selectivity. Drug Discov Today 20(6):718–735. https://doi.org/10.1016/j.drudis.2015.01.007
60. De Vreese R, D'Hooghe M (2017) Synthesis and applications of benzohydroxamic acid-based
histone deacetylase inhibitors. Eur J Med Chem 135:174–195. https://doi.org/10.1016/j.
ejmech.2017.04.013
61. Davenport AM, Huber FM, Hoelz A (2014) Structural and functional analysis of human
SIRT1. J Mol Biol 426(3):526–541. https://doi.org/10.1016/j.jmb.2013.10.009
62. Zhao X, Allison D, Condon B, Zhang FY, Gheyi T, Zhang AP, Ashok S, Russell M,
MacEwan I, Qian YW, Jamison JA, Luz JG (2013) The 2.5 angstrom crystal structure of the
SIRT1 catalytic domain bound to nicotinamide adenine dinucleotide (NAD(+)) and an indole
(EX527 analogue) reveals a novel mechanism of histone deacetylase inhibition. J Med Chem
56(3):963–969. https://doi.org/10.1021/jm301431y
63. Finnin MS, Donigian JR, Pavletich NP (2001) Structure of the histone deacetylase SIRT2. Nat
Struct Biol 8(7):621–625. https://doi.org/10.1038/89668
64. Moniot S, Schutkowski M, Steegborn C (2013) Crystal structure analysis of human Sirt2
and its ADP-ribose complex. J Struct Biol 182(2):136–143. https://doi.org/10.1016/j.jsb.2013.
02.012
Structure-Based Design of Epigenetic Inhibitors
479