MM-PBSA
Molecular mechanics Poisson-Boltzmann surface area
NAD
+
Nicotinamide adenine dinucleotide
NCI
National Cancer Institute
PAO
Plant amine oxidase
PDB
Protein Data Bank
PHD
Prolyl hydroxylase domain-containing protein
PKMT
Protein lysine methyltransferase
PRMT
Protein arginine methyltransferase
QSAR
Quantitative structure-activity relationship
RMSE
Root-mean-square error
SAH
S-adenosylhomocysteine
SAM
S-adenosyl-L-methionine
SAR
Structure-activity relationship
SET
Su(var)3-9, Enhancer-of-zeste and Trithorax
SETD
SET domain-containing lysine methyltransferase
Sirt
Sirtuin
smHDAC8
Schistosoma mansoni HDAC8
SWIRM
SWI3p, Rsc8p, and Moira
TI
Thermodynamic integration
TCF4
Transcription factor 4
VS
Virtual screening
1 Introduction
The two major biochemical pathways of epigenetic regulation are DNA methylation
and posttranslational modifications of amino acids in histone proteins. Histone
modifications interact with each other and constitute a particular pattern of alterations in the chromatin structure, the so-called histone code [1]. Posttranslational
modifications of histones have been shown to participate in a wide array of cellular
processes. Regulations of these covalent modifications and their implications are
currently of great interest in the scientific community [2]. Although histone proteins
are under the control of various posttranslational modifications, such as acetylation,
acylation, methylation, phosphorylation, ubiquitination, or glycosylation, the focus
of most studies has been mainly on lysine acetylation/deacetylation and methylation/
demethylation. Over the last decade, many of the enzymes that regulate these histone
modifications have been identified and characterized on a molecular level. With
large effort, a wealth of 3D structures of epigenetic targets has been determined,
which helped to understand the different epigenetic targets and their regulation on a
molecular level. From the early discovery of histone deacetylase inhibitors, such as
trichostatin A, to the more recent discovery of novel histone-modifying enzyme
Structure-Based Design of Epigenetic Inhibitors
457
Molecular mechanics Poisson-Boltzmann surface area
NAD
+
Nicotinamide adenine dinucleotide
NCI
National Cancer Institute
PAO
Plant amine oxidase
PDB
Protein Data Bank
PHD
Prolyl hydroxylase domain-containing protein
PKMT
Protein lysine methyltransferase
PRMT
Protein arginine methyltransferase
QSAR
Quantitative structure-activity relationship
RMSE
Root-mean-square error
SAH
S-adenosylhomocysteine
SAM
S-adenosyl-L-methionine
SAR
Structure-activity relationship
SET
Su(var)3-9, Enhancer-of-zeste and Trithorax
SETD
SET domain-containing lysine methyltransferase
Sirt
Sirtuin
smHDAC8
Schistosoma mansoni HDAC8
SWIRM
SWI3p, Rsc8p, and Moira
TI
Thermodynamic integration
TCF4
Transcription factor 4
VS
Virtual screening
1 Introduction
The two major biochemical pathways of epigenetic regulation are DNA methylation
and posttranslational modifications of amino acids in histone proteins. Histone
modifications interact with each other and constitute a particular pattern of alterations in the chromatin structure, the so-called histone code [1]. Posttranslational
modifications of histones have been shown to participate in a wide array of cellular
processes. Regulations of these covalent modifications and their implications are
currently of great interest in the scientific community [2]. Although histone proteins
are under the control of various posttranslational modifications, such as acetylation,
acylation, methylation, phosphorylation, ubiquitination, or glycosylation, the focus
of most studies has been mainly on lysine acetylation/deacetylation and methylation/
demethylation. Over the last decade, many of the enzymes that regulate these histone
modifications have been identified and characterized on a molecular level. With
large effort, a wealth of 3D structures of epigenetic targets has been determined,
which helped to understand the different epigenetic targets and their regulation on a
molecular level. From the early discovery of histone deacetylase inhibitors, such as
trichostatin A, to the more recent discovery of novel histone-modifying enzyme
Structure-Based Design of Epigenetic Inhibitors
457