Muutke küpsiste eelistusi

E-raamat: Epigenetic Drug Discovery

Edited by (University of Halle-Wittenberg, Germany), Series edited by (Aachen, Germany), Series edited by (University of Dusseldorf, Ge), Edited by (Albert Ludwigs University, Freiburg, Germany), Series edited by (Laboratorios Dr. Esteve, Barcelona, Spain)
Teised raamatud teemal:
  • Formaat - PDF+DRM
  • Hind: 191,42 €*
  • * hind on lõplik, st. muud allahindlused enam ei rakendu
  • Lisa ostukorvi
  • Lisa soovinimekirja
  • See e-raamat on mõeldud ainult isiklikuks kasutamiseks. E-raamatuid ei saa tagastada.
  • Raamatukogudele
Epigenetic Drug DiscoverySuurem pilt
Teised raamatud teemal:

DRM piirangud

  • Kopeerimine (copy/paste):

    ei ole lubatud

  • Printimine:

    ei ole lubatud

  • Kasutamine:

    Digitaalõiguste kaitse (DRM)
    Kirjastus on väljastanud selle e-raamatu krüpteeritud kujul, mis tähendab, et selle lugemiseks peate installeerima spetsiaalse tarkvara. Samuti peate looma endale  Adobe ID Rohkem infot siin. E-raamatut saab lugeda 1 kasutaja ning alla laadida kuni 6'de seadmesse (kõik autoriseeritud sama Adobe ID-ga).

    Vajalik tarkvara
    Mobiilsetes seadmetes (telefon või tahvelarvuti) lugemiseks peate installeerima selle tasuta rakenduse: PocketBook Reader (iOS / Android)

    PC või Mac seadmes lugemiseks peate installima Adobe Digital Editionsi (Seeon tasuta rakendus spetsiaalselt e-raamatute lugemiseks. Seda ei tohi segamini ajada Adober Reader'iga, mis tõenäoliselt on juba teie arvutisse installeeritud )

    Seda e-raamatut ei saa lugeda Amazon Kindle's. 

This broad view of epigenetic approaches in drug discovery combines methods and strategies with individual targets, including new and largely unexplored ones such as sirtuins and methyl-lysine reader proteins.
Presented in three parts - Introduction to Epigenetics, General Aspects and Methodologies, and Epigenetic Target Classes - it covers everything any drug researcher would need in order to know about targeting epigenetic mechanisms of disease.
Epigenetic Drug Discovery is an important resource for medicinal chemists, pharmaceutical researchers, biochemists, molecular biologists, and molecular geneticists.
Part I Introduction-Epigenetics 1(10)
1 Epigenetics: Moving Forward
3(8)
Lucia Altucci
1.1 Why This Enormously Increased Interest?
4(1)
1.2 Looking Forward to New Avenues of Epigenetics
5(2)
Acknowledgments
7(1)
References
7(4)
Part II General Aspects/Methodologies 11(142)
2 Structural Biology of Epigenetic Targets: Exploiting Complexity
13(32)
Martin Marek
Tajith B. Shaik
Christophe Romier
2.1 Introduction
13(1)
2.2 DNA Methylases: The DNMT3A-DNMT3L-H3 and DNMT1-USP7 Complexes
14(2)
2.3 Histone Arginine Methyltransferases: The PRMT5-MEP50 Complex
16(1)
2.4 Histone Lysine Methyltransferases: The MLL3-RBBP5-ASH2L and the PRC2 Complexes
17(4)
2.5 Histone Lysine Ubiquitinylases: The PRC1 Complex
21(1)
2.6 Histone Lysine Deubiquitinylases: The SAGA Deubiquitination Module
22(2)
2.7 Histone Acetyltransferases: The MSL1 and NUA4 Complexes
24(2)
2.8 Histone Deacetylases: HDAC1-MTA1 and HDAC3-SMRT Complexes and HDAC6
26(2)
2.9 Histone Variants and Histone Chaperones: A Complex and Modular Interplay
28(3)
2.10 ATP-Dependent Remodelers: CHD1, ISWI, SNF2, and the SNF2-Nucleosome Complex
31(4)
2.11 Epigenetic Readers: Histone Crotonylation Readers and the 53BP1-Nucleosome (H2AK15Ub-H4K20me2) Complex
35(2)
2.12 Conclusions
37(1)
Acknowledgments
38(1)
References
38(7)
3 Computer-based Lead Identification for Epigenetic Targets
45(34)
Chiara Luise
Tino Heimburg
Berin Karaman
Dina Robaa
Wolfgang Sippl
3.1 Introduction
45(1)
3.2 Computer-based Methods in Drug Discovery
46(3)
3.2.1 Pharmacophore-based Methods
46(1)
3.2.2 QSAR
47(1)
3.2.3 Docking
47(1)
3.2.4 Virtual Screening
48(1)
3.2.5 Binding Free Energy Calculation
49(1)
3.3 Histone Deacetylases
49(9)
3.3.1 Zinc-Dependent HDACs
49(5)
3.3.2 Sirtuins
54(4)
3.4 Histone Methyltransferases
58(3)
3.5 Histone Demethylases
61(5)
3.5.1 LSD1 (KDM1A)
62(2)
3.5.2 Jumonji Histone Demethylases
64(2)
3.6 Summary
66(1)
Acknowledgments
66(1)
References
67(12)
4 Mass Spectrometry and Chemical Biology in Epigenetics Drug Discovery
79(28)
Christian Feller
David Weigt
Carsten Hopf
4.1 Introduction: Mass Spectrometry Technology Used in Epigenetic Drug Discovery
79(6)
4.1.1 Mass Spectrometry Workflows for the Analysis of Proteins
80(3)
4.1.2 Mass Spectrometry Imaging
83(2)
4.2 Target Identification and Selectivity Profiling: Chemoproteomics
85(4)
4.2.1 Histone Deacetylase and Acetyltransferase Chemoproteomics
87(1)
4.2.2 Bromodomain Chemoproteomics
88(1)
4.2.3 Demethylase Chemoproteomics
88(1)
4.2.4 Methyltransferase Chemoproteomics
89(1)
4.3 Characterization of Epigenetic Drug Target Complexes and Reader Complexes Contributing to Drug's Mode of Action
89(2)
4.3.1 Immunoaffinity Purification of Native Protein Complexes
89(1)
4.3.2 Immunoaffinity Purification with Antibodies Against Epitope Tags
90(1)
4.3.3 Affinity Enrichment Using Histone Tail Peptides as Bait
91(1)
4.4 Elucidation of a Drug's Mode of Action: Analysis of Histone Posttranslational Modifications by MS-Based Proteomics
91(6)
4.4.1 Histone Modification MS Workflows
92(3)
4.4.2 Application of Histone MS Workflows to Characterize Epigenetic Drugs
95(2)
4.5 Challenges and New Trends
97(2)
4.5.1 Challenges and Trends in MS Analysis of Histone PTMs
97(1)
4.5.2 High-Throughput Mass Spectrometry-Based Compound Profiling in Epigenetic Drug Discovery
98(1)
4.5.3 Mass Spectrometry Imaging of Drug Action
98(1)
Acknowledgments
99(1)
References
99(8)
5 Peptide Microarrays for Epigenetic Targets
107(26)
Alexandra Schutkowski
Diana Kalbas
Ulf Reimer
Mike Schutkowski
5.1 Introduction
107(3)
5.2 Applications of Peptide Microarrays for Epigenetic Targets
110(14)
5.2.1 Profiling of Substrate Specificities of Histone Code Writers
110(4)
5.2.2 Profiling of Substrate Specificities of Histone Code Erasers
114(3)
5.2.3 Profiling of Binding Specificities of PTM-specific Antibodies and Histone Code Readers
117(1)
5.2.3.1 Profiling of Specificities of PTM-specific Antibodies
118(1)
5.2.3.2 Profiling of Binding Specificities of Histone Code Readers
119(2)
5.2.4 Peptide Microarray-based Identification of Upstream Kinases and Phosphorylation Sites for Epigenetic Targets
121(3)
5.3 Conclusion and Outlook
124(1)
Acknowledgment
124(1)
References
124(9)
6 Chemical Probes
133(20)
Amy Donner
Heather King
Paul E. Brennan
Moses Moustakim
William J. Zuercher
6.1 Chemical Probes Are Privileged Reagents for Biological Research
133(8)
6.1.1 Best Practices for the Generation and Selection of Chemical Probes
134(2)
6.1.2 Best Practices for Application of Chemical Probes
136(1)
6.1.3 Cellular Target Engagement
137(1)
6.1.3.1 Fluorescence Recovery After Photobleaching (FRAP)
138(1)
6.1.3.2 Affinity Bead-Based Proteomics
138(1)
6.1.3.3 Cellular Thermal Shift Assay (CETSA)
139(1)
6.1.3.4 Bioluminescence Resonance Energy Transfer
139(2)
6.2 Epigenetic Chemical Probes
141(6)
6.2.1 Histone Acetylation and Bromodomain Chemical Probes
141(1)
6.2.1.1 CBP/p300 Bromodomain Chemical Probes
144(1)
6.2.1.2 Future Applications of Bromodomain Chemical Probes
147(1)
6.3 Summary
147(1)
References
148(5)
Part III Epigenetic Target Classes 153(324)
7 Inhibitors of the Zinc-Dependent Histone Deacetylases
155(30)
Helle M.E. Kristensen
Andreas S. Madsen
Christian A. Olsen
7.1 Introduction: Histone Deacetylases
155(3)
7.2 Histone Deacetylase Inhibitors
158(11)
7.2.1 Types of Inhibitors
158(2)
7.2.2 HDAC Inhibitors in Clinical Use and Development
160(9)
7.3 Targeting of HDAC Subclasses
169(8)
7.3.1 Class I Inhibitors
169(1)
7.3.1.1 HDAC1-3 Inhibitors
170(1)
7.3.1.2 HDAC Inhibitors Targeting HDAC8
173(1)
7.3.2 Class IIa Inhibitors
174(2)
7.3.3 Class IIb
176(1)
7.4 Perspectives
177(2)
References
179(6)
8 Sirtuins as Drug Targets
185(16)
Clemens Zwergel
Dante Rotili
Sergio Valente
Antonello Mai
8.1 Introduction
185(1)
8.2 Biological Functions of Sirtuins in Physiology and Pathology
185(3)
8.3 SIRT Modulators
188(4)
8.3.1 SIRT Inhibitors
188(1)
8.3.1.1 Small Molecules
188(1)
8.3.1.2 Peptides and Pseudopeptides
191(1)
8.3.2 SIRT Activators
191(1)
8.4 Summary and Conclusions
192(1)
References
193(8)
9 Selective Small-Molecule Inhibitors of Protein Methyltransferases
201(20)
H. Umit Kaniskan
Jian Jin
9.1 Introduction
201(1)
9.2 Protein Methylation
201(1)
9.3 Lysine Methyltransferases (PKMTs)
202(1)
9.4 Inhibitors of PKMTs
202(9)
9.4.1 Inhibitors of H3K9 Methyltransferases
202(2)
9.4.2 Inhibitors of H3K27 Methyltransferases
204(2)
9.4.3 Inhibitors of H3K4 and H3K36 Methyltransferases
206(2)
9.4.4 Inhibitors of H4K20 Methyltransferases
208(2)
9.4.5 Inhibitors of H3K79 Methyltransferases
210(1)
9.5 Protein Arginine Methyltransferases (PRMTs)
211(4)
9.5.1 Inhibitors of PRMT1
211(1)
9.5.2 Inhibitors of PRMT3
212(1)
9.5.3 Inhibitors of CARM1
213(1)
9.5.4 Inhibitors of PRMT5
214(1)
9.5.5 Inhibitors of PRMT6
214(1)
9.6 Concluding Remarks
215(1)
References
215(6)
10 LSD (Lysine-Specific Demethylase): A Decade-Long Trip from Discovery to Clinical Trials
221(42)
Adam Lee
M. Teresa Borrello
A. Ganesan
10.1 Introduction
221(2)
10.2 LSDs: Discovery and Mechanistic Features
223(2)
10.3 LSD Substrates
225(4)
10.4 LSD Function and Dysfunction
229(3)
10.5 LSD Inhibitors
232(19)
10.5.1 Irreversible Small Molecule LSD Inhibitors from MAO Inhibitors
233(8)
10.5.2 Reversible Small Molecule LSD Inhibitors
241(7)
10.5.3 Synthetic Macromolecular LSD Inhibitors
248(3)
10.6 Summary
251(2)
References
253(10)
11 JmjC-domain-Containing Histone Demethylases
263(34)
Christoffer Hojrup
Oliver D. Coleman
John-Paul Bukowski
Rasmus P. Clausen
Akane Kawamura
11.1 Introduction
263(9)
11.1.1 The LSD and JmjC Histone Lysine Demethylases
263(2)
11.1.2 Histone Lysine Methylation and the JmjC-KDMs
265(1)
11.1.3 The JmjC-KDMs in Development and Disease
266(6)
11.2 KDM Inhibitor Development Targeting the JmjC Domain
272(12)
11.2.1 2-Oxoglutarate Cofactor Mimicking Inhibitors
273(1)
11.2.1.1 Emulation of the Chelating α-Keto Acid Moiety in 2OG
273(1)
11.2.1.2 Bioisosteres of the Conserved 2OG C5-Carboxylic Acid-Binding Motif
273(2)
11.2.2 Histone Substrate-Competitive Inhibitors
275(1)
11.2.2.1 Small-Molecule Inhibitors
276(1)
11.2.2.2 Peptide Inhibitors
276(1)
11.2.3 Allosteric Inhibitors
276(1)
11.2.4 Inhibitors Targeting KDM Subfamilies
277(1)
11.2.4.1 KDM4 Subfamily-Targeted Inhibitors
277(1)
11.2.4.2 KDM4/5 Subfamily-Targeted Inhibitors
279(1)
11.2.4.3 KDM5 Subfamily-Targeted Inhibitors
280(1)
11.2.4.4 KDM6 Subfamily-Targeted Inhibitors
281(1)
11.2.4.5 KDM2/7-and KDM3-Targeted Inhibitors
282(1)
11.2.4.6 Generic JmjC-KDM Inhibitors
282(1)
11.2.5 Selectivity and Potency of JmjC-KDM Inhibition in Cells
283(1)
11.3 KDM Inhibitors Targeting the Reader Domains
284(2)
11.3.1 Plant Homeodomain Fingers (PHD Fingers)
284(2)
11.3.2 Tudor Domains
286(1)
11.4 Conclusions and Future Perspectives
286(1)
Acknowledgments
287(1)
References
287(10)
12 Histone Acetyltransferases: Targets and Inhibitors
297(50)
Gianluca Sbardella
12.1 Introduction
297(1)
12.2 Acetyltransferase Enzymes and Families
298(1)
12.3 The GNAT Superfamily
299(5)
12.3.1 KAT2A/GCN5 and KAT2B/PCAF
301(2)
12.3.2 KAT1/Hat1
303(1)
12.3.3 GCN5L1
304(1)
12.4 KAT3A/CBP and KAT3B/p300 Family
304(2)
12.5 MYST Family
306(3)
12.5.1 KAT5/Tip60
306(1)
12.5.2 KAT6A/MOZ, KAT6B/MORF, and KAT7/HBO1
307(1)
12.5.3 KAT8/MOF
307(1)
12.5.4 SAS2 and SAS3
308(1)
12.5.5 ESA1
308(1)
12.5.6 Other KATs
308(1)
12.6 KATs in Diseases
309(3)
12.7 KAT Modulators
312(21)
12.7.1 Bisubstrate Inhibitors
313(2)
12.7.2 Natural Products and Synthetic Analogues and Derivatives
315(6)
12.7.3 Synthetic Compounds
321(7)
12.7.4 Compounds Targeting Protein-Protein Interaction Domains
328(5)
12.8 Conclusion
333(1)
References
334(13)
13 Bromodomains: Promising Targets for Drug Discovery
347(36)
Mehrosh Pervaiz
Pankaj Mishra
Stefan Gunther
13.1 Introduction
347(1)
13.2 The Human Bromodomain Family
348(5)
13.2.1 Structural Features of the Human BRD Family
348(1)
13.2.1.1 The Kac Binding Site
348(1)
13.2.1.2 Druggability of the Human BRD Family
350(2)
13.2.2 Functions of Bromodomain-containing Proteins
352(1)
13.3 Bromodomains and Diseases
353(4)
13.3.1 The BET Family
354(2)
13.3.2 Non-BET Proteins
356(1)
13.4 Methods for the Identification of Bromodomain Inhibitors
357(7)
13.4.1 High-throughput Screening (HTS)
357(2)
13.4.2 Fragment-based Lead Discovery
359(1)
13.4.3 Structure-based Drug Design
359(3)
13.4.4 Virtual Screening
362(1)
13.4.4.1 Structure-based Virtual Screening
362(1)
13.4.4.2 Ligand-based Virtual Screening
362(1)
13.4.4.3 Pharmacophore Modeling
363(1)
13.4.4.4 Substructure and Similarity Search
363(1)
13.5 Current Bromodomain Inhibitors
364(1)
13.6 Multi-target Inhibitors
365(4)
13.6.1 Dual Kinase-Bromodomain Inhibitors
365(4)
13.6.2 Dual BET/HDAC Inhibitors
369(1)
13.7 Proteolysis Targeting Chimeras (PROTACs)
369(2)
13.8 Conclusions
371(1)
Acknowledgments
372(1)
References
372(11)
14 Lysine Reader Proteins
383(38)
Johannes Bacher
Dina Robaa
Chiara Luise
Wolfgang Sippl
Manfred Jung
14.1 Introduction
383(2)
14.2 The Royal Family of Epigenetic Reader Proteins
385(15)
14.2.1 The MBT Domain
385(5)
14.2.2 The PWWP Domain
390(2)
14.2.3 The Tudor Domain
392(3)
14.2.4 The Chromodomain
395(5)
14.3 The PHD Finger Family of Epigenetic Reader Proteins
400(2)
14.4 The WD40 Repeat Domain Family
402(7)
14.5 Conclusion and Outlook
409(1)
Acknowledgment
409(1)
References
409(12)
15 DNA-modifying Enzymes
421(36)
Martin Roatsch
Dina Robaa
Michael Lubbert
Wolfgang Sippl
Manfred Jung
15.1 Introduction
421(1)
15.2 DNA Methylation
422(2)
15.3 Further Modifications of Cytosine Bases
424(2)
15.4 DNA Methyltransferases: Substrates and Structural Aspects
426(4)
15.5 Mechanism of Enzymatic DNA Methylation
430(1)
15.6 Physiological Role of DNA Methylation
431(1)
15.7 DNA Methylation in Disease
432(1)
15.8 DNMT Inhibitors
433(8)
15.8.1 Nucleoside-mimicking DNMT Inhibitors
433(3)
15.8.2 Non-nucleosidic DNMT Inhibitors
436(5)
15.9 Therapeutic Applications of DNMT Inhibitors
441(1)
15.10 Conclusion
442(1)
Acknowledgment
443(1)
References
443(14)
16 Parasite Epigenetic Targets
457(20)
Raymond J. Pierce
Jamal Khalife
16.1 Introduction: The Global Problem of Parasitic Diseases and the Need for New Drugs
457(1)
16.2 Parasite Epigenetic Mechanisms
458(7)
16.2.1 DNA Methylation
459(1)
16.2.2 Histone Posttranslational Modifications
460(2)
16.2.3 Histone-modifying Enzymes in Parasites
462(1)
16.2.4 HMEs Validated as Therapeutic Targets
462(2)
16.2.5 Structure-based Approaches for Defining Therapeutic Targets
464(1)
16.3 Development of Epi-drugs for Parasitic Diseases
465(3)
16.3.1 Repurposing of Existing Epi-drugs
466(1)
16.3.2 Candidates from Phenotypic or High-throughput Screens
467(1)
16.3.3 Structure-based Development of Selective Inhibitors
467(1)
16.4 Conclusions
468(1)
Acknowledgments
469(1)
References
469(8)
Index 477
Wolfgang Sippl, PhD, holds the chair in Medicinal Chemistry at the Institute of Pharmacy at the Martin Luther University Halle-Wittenberg.

Manfred Jung, PhD, is a full professor for Pharmaceutical Chemistry at the University of Freiburg and the co-chairman of the SFB research project "Medical Epigenetics".
Lisainfo e-raamatute kohta Lisainfo e-raamatute kohta
Püsilink: https://www.kriso.ee/db/97835278092882e.html