Computational and structural approaches to drug discovery: ligand-protein interactions
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| Format: | Book |
|---|---|
| Language: | English |
| Published: |
Cambridge
RSC Publishing
2008
|
| Series: | RSC biomolecular sciences
|
| Subjects: | |
| Online Access: | Inhaltsverzeichnis |
| Item Description: | Includes bibliographical references and index. - Formerly CIP |
| Physical Description: | XVII,382 S. Ill., graph. Darst. 25cm |
| ISBN: | 9780854043651 |
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MARC
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| 245 | 1 | 0 | |a Computational and structural approaches to drug discovery |b ligand-protein interactions |c edited by Robert M. Stroud ... |
| 264 | 1 | |a Cambridge |b RSC Publishing |c 2008 | |
| 300 | |a XVII,382 S. |b Ill., graph. Darst. |c 25cm | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 490 | 0 | |a RSC biomolecular sciences | |
| 500 | |a Includes bibliographical references and index. - Formerly CIP | ||
| 650 | 4 | |a Computer-Aided Design | |
| 650 | 4 | |a Drug Design | |
| 650 | 4 | |a Drug development | |
| 650 | 4 | |a Drugs |x Structure-activity relationships | |
| 650 | 4 | |a Ligands | |
| 650 | 4 | |a Ligands (Biochemistry) | |
| 650 | 4 | |a Protein engineering | |
| 650 | 4 | |a Proteins |x chemistry | |
| 650 | 0 | 7 | |a Ligand |g Biochemie |0 (DE-588)4606532-5 |2 gnd |9 rswk-swf |
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| 689 | 0 | 0 | |a Arzneimitteldesign |0 (DE-588)4278218-1 |D s |
| 689 | 0 | 1 | |a Ligand |g Biochemie |0 (DE-588)4606532-5 |D s |
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| 700 | 1 | |a Stroud, Robert |e Sonstige |4 oth | |
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| 999 | |a oai:aleph.bib-bvb.de:BVB01-016498789 | ||
Record in the Search Index
| _version_ | 1804137650071797760 |
|---|---|
| adam_text | Contents
Section
1 Overveiw
Chapter
1
Facing the Wall in Computationally Based Approaches to
Drug Discovery
Janet S. Finer-Moore, Jeff Blaney and Robert M. Stroud
1.1
The Promise, and the Problem
3
1.2
Current Limitations in Structure-guided Lead Design
5
1.3
Lessons in Structure-based Drug Design from
Thymidylate Synthase
7
1.3.1
Mechanism-based Inhibitors and
Enzyme-catalyzed Therapeutics
7
1.3.2
Iterative Structure-based Drug Design
8
1.3.3
Docking, Fragments and Optimizability
8
1.4
New Developments in Structure-based Drug-design
Methods
13
1.4.1
Fragment-based Methods
13
1.4.2
Identifying Drug Target Sites on a Protein
16
1.4.3
Targeting Protein-Protein Interactions
17
1.4.4
Computational Docking to Nominated Sites
18
1.5
Conclusion
19
References
20
Chapter
2
The Changing Landscape in Drug Discovery
Hugo Kubinyi
2.1
Introduction
24
2.2
QSAR
-
Understanding Without Prediction
25
2.3
Gene Technology
—
from Mice to Humans
27
2.4
Combinatorial Library Design
-
Driven by
Medicinal Chemistry
28
2.5
Docking and Scoring
-
Solved and Unsolved Problems
32
2.6
Virtual Screening
-
the Road to Success
35
2.7
Fragment-based and Combinatorial Design
-
A New
Challenge
37
Contents xi
2.8
Summary and Conclusions
38
References
41
Section
2
Structure-Based Design
Chapter
3
Purine
Nucleoside Phosphorylase
Yang Zhang and Steven E. Ealick
3.1
Introduction
49
3.2
Three-dimensional Structures of PNPs
51
3.3
Related Enzymes of the PNP Family
54
3.4
PNP Active Sites
55
3.5
Human PNP Inhibitors
58
3.6
Other Applications of Molecular Design to PNP
62
3.7
Applications of Molecular Design to Enzymes
Related to PNP
64
3.8
PNP Inhibitors and Clinical Trials
65
3.9
Conclusions and Future Directions
66
Note Added in Proof
66
References
67
Chapter
4
Application and Limitations of
Х
-Ray Crystallographic
Data in Structure-Guided Ligand and Drug Design
Andrew M. Davis, Simon J. Teague and Gerard J. Kleywegt
4.1
Introduction
73
4.2
Structure-guided Ligand Design and Drug Design
74
4.3
Some Limitations in the Use of X-ray Data
79
4.3.1
Basic Crystallography Terms
79
4.3.2
Uncertainty in the Identity or Location of
Protein or Ligand Atoms
83
4.3.3
Effect of Crystallization Conditions
86
4.3.4
Identification and Location of Water
87
4.4
Macromolecular Structures to Determine
Small-molecule Structures
88
4.5
Assessing the Validity of Structure Models
89
4.6
Summary and Outlook
90
References
91
Chapter
5
Dealing with Bound Waters in a Site: Do they Leave or Stay?
Donald
Hamelberg
and J. Andrew McCammon
5.1
Introduction
95
5.2
Localized Water Molecules in Binding Sites of Proteins
96
5.3
Identifying Localized Water Molecules from
Computer Simulations
99
XU
Contents
5.4
Calculation of Free-energy Cost of Displacing a
Site-bound Water Molecule
101
5.5
Inclusion of Explicit Water Molecules in Drug
Discovery
104
Acknowledgements
106
References
106
Chapter
6
Knowledge-Based Methods in Structure-Based Design
Marcel L. Verdonk and Wijnand T.M. Mooij
6.1
Introduction
111
6.2
Atom-based Potentials
111
6.3
Group-based Potentials
112
6.4
Methodologies
114
6.4.1
The Reference State
115
6.4.2
Volume Corrections
116
6.5
Applications
117
6.5.1
Visualization and Interaction Hot Spots
117
6.5.2
Docking and Scoring
118
6.5.3
De Novo
Design
120
6.5.4
Targeted Scoring Functions
120
6.6
Discussion
121
6.7
Conclusion
123
References
123
Chapter
7
Combating Drug Resistance
—
Identifying Resilient Molecular
Targets and Robust Drugs
Celia A.
Schiffer
7.1
Introduction
7.2
Resilient Targets and Robust Drugs
7.3
Example of
HIV-1
Protease: Substrate Recognition vs.
Drug Resistance
7.4
Implications for Future Structure-based Drug Design
Acknowledgements
References
Section
3
Docking
Chapter
8
Docking Algorithms and Scoring Functions; State-of-the-Art
and Current Limitations
Gregory L. Warren, Catherine E. Peishoff and Martha
S. Head
127
128
129
132
132
132
.1
Introduction
8.1.1
Binding Mode Prediction
137
138
Contents xiii
8.1.2 Virtual
Screening for Lead
Identification 139
8.1.3
Potency Prediction for Lead Optimization
139
8.2
A Brief Review of Recent Docking Evaluations
140
8.3
What these Evaluations Tell us about the Performance
of Docking Algorithms
143
8.3.1
Binding Mode Predictions
143
8.3.2
Virtual Screening
144
8.3.3
Affinity Prediction
145
8.4
How an Ideal Evaluation Data Set Might be
Structured
147
8.4.1
Binding Mode Prediction
147
8.4.2
Virtual Screening
148
8.4.3
Affinity Prediction
148
8.5
Concluding Remarks
149
8.5.1
Binding Mode Prediction
149
8.5.2
Virtual Screening
150
8.5.3
Rank Order by Affinity
151
8.5.4
The State-of-the-art
152
References
153
Chapter
9
Application of Docking Methods to Structure-Based Drug
Design
Demetri
T. Moustakas
9.1
Introduction
155
9.2
Docking Methods, Capabilities and Limitations
156
9.2.1
Molecule Preparation
156
9.2.2
Sampling Methods
157
9.2.3
Scoring Methods
160
9.2.4
Managing Errors in Docking
162
9.3
How is Docking Applied to Drug Design?
164
9.3.1
Drug Target Selection and Characterization
165
9.3.2
Lead Compound Discovery
168
9.3.3
Lead Compound Optimization
171
9.4
Summary
172
References
172
Chapter
10
Strength in Flexibility: Modeling Side-Chain
Conformational Change in Docking and Screening
Leslie A.
Kuhn
10.1
Introduction
181
10.2
Background
181
10.2.1
Improving Docking and Screening
Through Side-chain Flexibility Modeling
181
xjv
Contents
10.2.2
Enhancing Target Specificity Through
Flexibility Modeling
182
10.3
Approaches
183
10.3.1
The State of the Art in Modeling Protein
Side-chain Flexibility
183
10.3.2
Learning from Nature: Observing Side-chain
Motions Upon Ligand Binding
185
10.4
The Future: Knowledge-based Modeling of Side-chain
Motions
189
Acknowledgements
189
References
190
Chapter
11
Avoiding the Rigid Receptor: Side-Chain Rotamers
Amy C. Anderson
11.1
Introduction
192
11.2
Rotamer Libraries
194
11.3
Successful Applications of Rotamer Libraries in
Drug Design
195
11.3.1
Aspartic Acid Protease Inhibitors
195
11.3.2
Matrix Metalloproteinase-l Inhibitors
195
11.3.3
Thymidylate Synthase Inhibitors
199
11.3.4
Protein Tyrosine Phosphatase IB Inhibitors
200
11.3.5 HIV
Protease Drug-resistant Mutants Bound
to Inhibitors
201
11.3.6
Trypsin-benzamidine and Phosphocholine-
McPC
603 201
11.4
Conclusions
202
Acknowledgements
202
References
202
Section
4
Screening
Chapter
12
Computational Prediction of Aqueous Solubility, Oral
Bioavailability, P450 Activity and hERG Channel
Blockade
David E. Clark
12.1
Introduction
207
12.2
Aqueous Solubility
208
12.3
Oral Bioavailability
211
12.4
Cytochrome P450 Activity
212
12.5
hERG Channel Blockade
215
12.6
Conclusions
219
References
220
Contents xv
Chapter
13
Shadows on Screens
Brian K. Shoichet, Brian Y. Feng and Kristin E.D. Coan
13.1
Introduction
223
13.2
Phenomenology of Aggregation
224
13.3
What Sort of Compounds Aggregate?
227
13.4
Mechanism of Aggregation-based Inhibition
232
13.5
A Rapid Counter-screen for Aggregation-based Inhibitors
233
13.6
Biological Implications?
239
13.7
The Spirit-haunted World of Screening
239
Acknowledgements
240
References
240
Chapter
14
Iterative Docking Strategies for Virtual Ligand Screening
Albert E. Beuscher IV and Arthur J. Olson
14.1
Introduction
242
14.2
AutoDock Background
243
14.2.1
Scoring Function
243
14.2.2
Search Function
244
14.2.3
AutoDockTools
244
14.2.4
AutoDockTools Analysis
245
14.3
Diversity-based Virtual Screening Studies
246
14.3.1
AICAR Transformylase
246
14.3.2
Protein Phosphatase 2C
246
14.4
Comparison with Existing VLS Strategies
253
14.4.1
Hierarchical VLS
256
14.4.2
Monolithic VLS Strategy
258
14.5
Other AutoDock VLS Studies
259
14.5.1
Acetylcholine
Esterase
Peripheral
Anionie
Site
259
14.5.2
Human P2Y! Receptor
260
14.6
Diversity-based vs. Issues
260
14.6.1
Library Choice
260
14.6.2
Similarity Search
261
14.6.3
Apo
Versus Ligand-bound Docking Models
262
14.6.4
Binding Site Choices
263
14.7
Future Work
264
References
264
Chapter
15
Challenges and Progresses in Calculations of Binding Free
Energies
-
What Does it Take to Quantify Electrostatic
Contributions to Protein-Ligand Interactions?
Mitsunori
Kato,
Sonja Braun-Sand
and Arieh
Warshei
15.1
Introduction
268
15.2
Computational Strategies
269
xv¡
Contents
15.2.1
Free-energy Perturbation, Linear Response
Approximation and Potential of Mean Force
Calculations by All-atom Models
269
15.2.2
Proper and Improper Treatments of
Long-range Effects in All-atom Models
273
15.2.3
Calculations of Electrostatic Energies by
Simplified Models
274
15.3
Calculating Binding Free Energies
277
15.3.1
Studies of Drug Mutations by FEP
Approaches
277
15.3.2
Evaluation of Absolute Binding Energies
by the LRA and LIE Approaches
278
15.3.3
Using Semi-macroscopic and Macroscopic
Approaches in Studies of Ligand Binding
279
15.3.4
Protein-protein Interactions
281
15.4
Challenges and New Advances
282
15.5
Perspectives
285
Acknowledgement
285
References
285
Section
5
Fragment-Based Design
Chapter
16
Discovery and Extrapolation of Fragment Structures
towards Drug Design
Alessio
Ciulii,
Tom
L.
Blundeli
and Chris Abell
16.1
Structure-based Approaches to Drug Discovery
293
16.2
Properties of Molecular Fragments
294
16.3
From Molecular Fragments to Drug Leads
296
16.3.1
Fragment Growing
296
16.3.2
Fragment Linking
297
16.3.3
Fragment Assembly
299
16.4
Screening and Identification of Fragments
300
16.5
X-ray Crystallography for Fragment-based
Lead Identification
301
16.6
NMR Spectroscopy
302
16.6.1
Protein-based Methods: Structure-activity
Relationship by NMR
302
16.6.2
Ligand-based Methods
303
16.7
Mass Spectrometry
306
16.7.1
Covalent Mass Spectrometric Methods
306
16.7.2
Non-covalent Mass Spectrometric Methods
307
16.7.3
Looking at the Protein or the Ligand
308
16.8
Thermal Shift
309
16.9
Isothermal
Titration
Calorimetry
309
16.10
Surface Plasmon Resonance
310
Contents xvii
16.11
Concluding Remarks
311
Acknowledgements
311
References
311
Chapter
17
A Link Means a Lot:
Disillude
Tethering in Structure-Based
Drug Design
Jeanne A. Hardy
17.1
Introduction: What is Disulfide Tethering?
319
17.2
Success of Native
Cysteine
Tethering
323
17.3
Role of Structure in Engineered-cysteine Tethering
325
17.4
Cooperative Tethering
328
17.5
Extended Tethering
330
17.6
Breakaway Tethering
333
17.7
Discovery of Novel Allosteric Sites with Tethering
335
17.8
Tethering as a Validation Tool
339
17.9
Tethering vs. Traditional Medicinal Chemistry
340
17.10
Tethering in Structural Determination
341
17.11
The Challenge of Covalency
342
17.12 Hydrophobie
Binders
343
17.13
Conclusions: The Future of Tethering
344
References
345
Chapter
18
The Impact of Protein Kinase Structures on Drug Discovery
Chao
Zhang and Sung-Hou Kim
18.1
Introduction
. 349
18.2
The Hinge Region and the Concept of Kinase
Inhibitor Scaffold
351
18.3
High-throughput Crystallography for the Discovery
of Novel Scaffolds
353
18.3.1
High Potency-High Specificity-High
Molecular (H3) Weight Screening
353
18.3.2
Low Potency-Low Specificity-Low
Molecular Weight (L3) Screening
354
18.4
The Gatekeeper Residue and the Selectivity Pocket
355
18.5
The Conformational States of the
DFG
Motif and the
Opening of the Back Pocket
357
18.6
Allosteric Inhibitors, Non-ATP Competitive
Inhibitors, and Irreversible Inhibitors
359
18.7
Discovering Kinase Inhibitors in a 500-Dimensional
Space
360
Acknowledgement
361
References
361
Subject Index
366
|
| adam_txt |
Contents
Section
1 Overveiw
Chapter
1
Facing the Wall in Computationally Based Approaches to
Drug Discovery
Janet S. Finer-Moore, Jeff Blaney and Robert M. Stroud
1.1
The Promise, and the Problem
3
1.2
Current Limitations in Structure-guided Lead Design
5
1.3
Lessons in Structure-based Drug Design from
Thymidylate Synthase
7
1.3.1
Mechanism-based Inhibitors and
Enzyme-catalyzed Therapeutics
7
1.3.2
Iterative Structure-based Drug Design
8
1.3.3
Docking, Fragments and Optimizability
8
1.4
New Developments in Structure-based Drug-design
Methods
13
1.4.1
Fragment-based Methods
13
1.4.2
Identifying Drug Target Sites on a Protein
16
1.4.3
Targeting Protein-Protein Interactions
17
1.4.4
Computational Docking to Nominated Sites
18
1.5
Conclusion
19
References
20
Chapter
2
The Changing Landscape in Drug Discovery
Hugo Kubinyi
2.1
Introduction
24
2.2
QSAR
-
Understanding Without Prediction
25
2.3
Gene Technology
—
from Mice to Humans
27
2.4
Combinatorial Library Design
-
Driven by
Medicinal Chemistry
28
2.5
Docking and Scoring
-
Solved and Unsolved Problems
32
2.6
Virtual Screening
-
the Road to Success
35
2.7
Fragment-based and Combinatorial Design
-
A New
Challenge
37
Contents xi
2.8
Summary and Conclusions
38
References
41
Section
2
Structure-Based Design
Chapter
3
Purine
Nucleoside Phosphorylase
Yang Zhang and Steven E. Ealick
3.1
Introduction
49
3.2
Three-dimensional Structures of PNPs
51
3.3
Related Enzymes of the PNP Family
54
3.4
PNP Active Sites
55
3.5
Human PNP Inhibitors
58
3.6
Other Applications of Molecular Design to PNP
62
3.7
Applications of Molecular Design to Enzymes
Related to PNP
64
3.8
PNP Inhibitors and Clinical Trials
65
3.9
Conclusions and Future Directions
66
Note Added in Proof
66
References
67
Chapter
4
Application and Limitations of
Х
-Ray Crystallographic
Data in Structure-Guided Ligand and Drug Design
Andrew M. Davis, Simon J. Teague and Gerard J. Kleywegt
4.1
Introduction
73
4.2
Structure-guided Ligand Design and Drug Design
74
4.3
Some Limitations in the Use of X-ray Data
79
4.3.1
Basic Crystallography Terms
79
4.3.2
Uncertainty in the Identity or Location of
Protein or Ligand Atoms
83
4.3.3
Effect of Crystallization Conditions
86
4.3.4
Identification and Location of Water
87
4.4
Macromolecular Structures to Determine
Small-molecule Structures
88
4.5
Assessing the Validity of Structure Models
89
4.6
Summary and Outlook
90
References
91
Chapter
5
Dealing with Bound Waters in a Site: Do they Leave or Stay?
Donald
Hamelberg
and J. Andrew McCammon
5.1
Introduction
95
5.2
Localized Water Molecules in Binding Sites of Proteins
96
5.3
Identifying Localized Water Molecules from
Computer Simulations
99
XU
Contents
5.4
Calculation of Free-energy Cost of Displacing a
Site-bound Water Molecule
101
5.5
Inclusion of Explicit Water Molecules in Drug
Discovery
104
Acknowledgements
106
References
106
Chapter
6
Knowledge-Based Methods in Structure-Based Design
Marcel L. Verdonk and Wijnand T.M. Mooij
6.1
Introduction
111
6.2
Atom-based Potentials
111
6.3
Group-based Potentials
112
6.4
Methodologies
114
6.4.1
The Reference State
115
6.4.2
Volume Corrections
116
6.5
Applications
117
6.5.1
Visualization and Interaction 'Hot Spots'
117
6.5.2
Docking and Scoring
118
6.5.3
De Novo
Design
120
6.5.4
Targeted Scoring Functions
120
6.6
Discussion
121
6.7
Conclusion
123
References
123
Chapter
7
Combating Drug Resistance
—
Identifying Resilient Molecular
Targets and Robust Drugs
Celia A.
Schiffer
7.1
Introduction
7.2
Resilient Targets and Robust Drugs
7.3
Example of
HIV-1
Protease: Substrate Recognition vs.
Drug Resistance
7.4
Implications for Future Structure-based Drug Design
Acknowledgements
References
Section
3
Docking
Chapter
8
Docking Algorithms and Scoring Functions; State-of-the-Art
and Current Limitations
Gregory L. Warren, Catherine E. Peishoff and Martha
S. Head
127
128
129
132
132
132
.1
Introduction
8.1.1
Binding Mode Prediction
137
138
Contents xiii
8.1.2 Virtual
Screening for Lead
Identification 139
8.1.3
Potency Prediction for Lead Optimization
139
8.2
A Brief Review of Recent Docking Evaluations
140
8.3
What these Evaluations Tell us about the Performance
of Docking Algorithms
143
8.3.1
Binding Mode Predictions
143
8.3.2
Virtual Screening
144
8.3.3
Affinity Prediction
145
8.4
How an Ideal Evaluation Data Set Might be
Structured
147
8.4.1
Binding Mode Prediction
147
8.4.2
Virtual Screening
148
8.4.3
Affinity Prediction
148
8.5
Concluding Remarks
149
8.5.1
Binding Mode Prediction
149
8.5.2
Virtual Screening
150
8.5.3
Rank Order by Affinity
151
8.5.4
The State-of-the-art
152
References
153
Chapter
9
Application of Docking Methods to Structure-Based Drug
Design
Demetri
T. Moustakas
9.1
Introduction
155
9.2
Docking Methods, Capabilities and Limitations
156
9.2.1
Molecule Preparation
156
9.2.2
Sampling Methods
157
9.2.3
Scoring Methods
160
9.2.4
Managing Errors in Docking
162
9.3
How is Docking Applied to Drug Design?
164
9.3.1
Drug Target Selection and Characterization
165
9.3.2
Lead Compound Discovery
168
9.3.3
Lead Compound Optimization
171
9.4
Summary
172
References
172
Chapter
10
Strength in Flexibility: Modeling Side-Chain
Conformational Change in Docking and Screening
Leslie A.
Kuhn
10.1
Introduction
181
10.2
Background
181
10.2.1
Improving Docking and Screening
Through Side-chain Flexibility Modeling
181
xjv
Contents
10.2.2
Enhancing Target Specificity Through
Flexibility Modeling
182
10.3
Approaches
183
10.3.1
The State of the Art in Modeling Protein
Side-chain Flexibility
183
10.3.2
Learning from Nature: Observing Side-chain
Motions Upon Ligand Binding
185
10.4
The Future: Knowledge-based Modeling of Side-chain
Motions
189
Acknowledgements
189
References
190
Chapter
11
Avoiding the Rigid Receptor: Side-Chain Rotamers
Amy C. Anderson
11.1
Introduction
192
11.2
Rotamer Libraries
194
11.3
Successful Applications of Rotamer Libraries in
Drug Design
195
11.3.1
Aspartic Acid Protease Inhibitors
195
11.3.2
Matrix Metalloproteinase-l Inhibitors
195
11.3.3
Thymidylate Synthase Inhibitors
199
11.3.4
Protein Tyrosine Phosphatase IB Inhibitors
200
11.3.5 HIV
Protease Drug-resistant Mutants Bound
to Inhibitors
201
11.3.6
Trypsin-benzamidine and Phosphocholine-
McPC
603 201
11.4
Conclusions
202
Acknowledgements
202
References
202
Section
4
Screening
Chapter
12
Computational Prediction of Aqueous Solubility, Oral
Bioavailability, P450 Activity and hERG Channel
Blockade
David E. Clark
12.1
Introduction
207
12.2
Aqueous Solubility
208
12.3
Oral Bioavailability
211
12.4
Cytochrome P450 Activity
212
12.5
hERG Channel Blockade
215
12.6
Conclusions
219
References
220
Contents xv
Chapter
13
Shadows on Screens
Brian K. Shoichet, Brian Y. Feng and Kristin E.D. Coan
13.1
Introduction
223
13.2
Phenomenology of Aggregation
224
13.3
What Sort of Compounds Aggregate?
227
13.4
Mechanism of Aggregation-based Inhibition
232
13.5
A Rapid Counter-screen for Aggregation-based Inhibitors
233
13.6
Biological Implications?
239
13.7
The Spirit-haunted World of Screening
239
Acknowledgements
240
References
240
Chapter
14
Iterative Docking Strategies for Virtual Ligand Screening
Albert E. Beuscher IV and Arthur J. Olson
14.1
Introduction
242
14.2
AutoDock Background
243
14.2.1
Scoring Function
243
14.2.2
Search Function
244
14.2.3
AutoDockTools
244
14.2.4
AutoDockTools Analysis
245
14.3
Diversity-based Virtual Screening Studies
246
14.3.1
AICAR Transformylase
246
14.3.2
Protein Phosphatase 2C
246
14.4
Comparison with Existing VLS Strategies
253
14.4.1
Hierarchical VLS
256
14.4.2
Monolithic VLS Strategy
258
14.5
Other AutoDock VLS Studies
259
14.5.1
Acetylcholine
Esterase
Peripheral
Anionie
Site
259
14.5.2
Human P2Y! Receptor
260
14.6
Diversity-based vs. Issues
260
14.6.1
Library Choice
260
14.6.2
Similarity Search
261
14.6.3
Apo
Versus Ligand-bound Docking Models
262
14.6.4
Binding Site Choices
263
14.7
Future Work
264
References
264
Chapter
15
Challenges and Progresses in Calculations of Binding Free
Energies
-
What Does it Take to Quantify Electrostatic
Contributions to Protein-Ligand Interactions?
Mitsunori
Kato,
Sonja Braun-Sand
and Arieh
Warshei
15.1
Introduction
268
15.2
Computational Strategies
269
xv¡
Contents
15.2.1
Free-energy Perturbation, Linear Response
Approximation and Potential of Mean Force
Calculations by All-atom Models
269
15.2.2
Proper and Improper Treatments of
Long-range Effects in All-atom Models
273
15.2.3
Calculations of Electrostatic Energies by
Simplified Models
274
15.3
Calculating Binding Free Energies
277
15.3.1
Studies of Drug Mutations by FEP
Approaches
277
15.3.2
Evaluation of Absolute Binding Energies
by the LRA and LIE Approaches
278
15.3.3
Using Semi-macroscopic and Macroscopic
Approaches in Studies of Ligand Binding
279
15.3.4
Protein-protein Interactions
281
15.4
Challenges and New Advances
282
15.5
Perspectives
285
Acknowledgement
285
References
285
Section
5
Fragment-Based Design
Chapter
16
Discovery and Extrapolation of Fragment Structures
towards Drug Design
Alessio
Ciulii,
Tom
L.
Blundeli
and Chris Abell
16.1
Structure-based Approaches to Drug Discovery
293
16.2
Properties of Molecular Fragments
294
16.3
From Molecular Fragments to Drug Leads
296
16.3.1
Fragment Growing
296
16.3.2
Fragment Linking
297
16.3.3
Fragment Assembly
299
16.4
Screening and Identification of Fragments
300
16.5
X-ray Crystallography for Fragment-based
Lead Identification
301
16.6
NMR Spectroscopy
302
16.6.1
Protein-based Methods: Structure-activity
Relationship by NMR
302
16.6.2
Ligand-based Methods
303
16.7
Mass Spectrometry
306
16.7.1
Covalent Mass Spectrometric Methods
306
16.7.2
Non-covalent Mass Spectrometric Methods
307
16.7.3
Looking at the Protein or the Ligand
308
16.8
Thermal Shift
309
16.9
Isothermal
Titration
Calorimetry
309
16.10
Surface Plasmon Resonance
310
Contents xvii
16.11
Concluding Remarks
311
Acknowledgements
311
References
311
Chapter
17
A Link Means a Lot:
Disillude
Tethering in Structure-Based
Drug Design
Jeanne A. Hardy
17.1
Introduction: What is Disulfide Tethering?
319
17.2
Success of Native
Cysteine
Tethering
323
17.3
Role of Structure in Engineered-cysteine Tethering
325
17.4
Cooperative Tethering
328
17.5
Extended Tethering
330
17.6
Breakaway Tethering
333
17.7
Discovery of Novel Allosteric Sites with Tethering
335
17.8
Tethering as a Validation Tool
339
17.9
Tethering vs. Traditional Medicinal Chemistry
340
17.10
Tethering in Structural Determination
341
17.11
The Challenge of Covalency
342
17.12 Hydrophobie
Binders
343
17.13
Conclusions: The Future of Tethering
344
References
345
Chapter
18
The Impact of Protein Kinase Structures on Drug Discovery
Chao
Zhang and Sung-Hou Kim
18.1
Introduction
. 349
18.2
The Hinge Region and the Concept of Kinase
Inhibitor Scaffold
351
18.3
High-throughput Crystallography for the Discovery
of Novel Scaffolds
353
18.3.1
High Potency-High Specificity-High
Molecular (H3) Weight Screening
353
18.3.2
Low Potency-Low Specificity-Low
Molecular Weight (L3) Screening
354
18.4
The Gatekeeper Residue and the Selectivity Pocket
355
18.5
The Conformational States of the
DFG
Motif and the
Opening of the Back Pocket
357
18.6
Allosteric Inhibitors, Non-ATP Competitive
Inhibitors, and Irreversible Inhibitors
359
18.7
Discovering Kinase Inhibitors in a 500-Dimensional
Space
360
Acknowledgement
361
References
361
Subject Index
366 |
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| genre_facet | Patentschrift |
| id | DE-604.BV023314576 |
| illustrated | Illustrated |
| index_date | 2024-07-02T20:51:38Z |
| indexdate | 2024-07-09T21:15:40Z |
| institution | BVB |
| isbn | 9780854043651 |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-016498789 |
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| physical | XVII,382 S. Ill., graph. Darst. 25cm |
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| spelling | Computational and structural approaches to drug discovery ligand-protein interactions edited by Robert M. Stroud ... Cambridge RSC Publishing 2008 XVII,382 S. Ill., graph. Darst. 25cm txt rdacontent n rdamedia nc rdacarrier RSC biomolecular sciences Includes bibliographical references and index. - Formerly CIP Computer-Aided Design Drug Design Drug development Drugs Structure-activity relationships Ligands Ligands (Biochemistry) Protein engineering Proteins chemistry Ligand Biochemie (DE-588)4606532-5 gnd rswk-swf Arzneimittelentwicklung (DE-588)4143176-5 gnd rswk-swf Arzneimitteldesign (DE-588)4278218-1 gnd rswk-swf Proteindesign (DE-588)4346801-9 gnd rswk-swf (DE-588)4173536-5 Patentschrift gnd-content Arzneimitteldesign (DE-588)4278218-1 s Ligand Biochemie (DE-588)4606532-5 s Proteindesign (DE-588)4346801-9 s DE-604 Arzneimittelentwicklung (DE-588)4143176-5 s Stroud, Robert Sonstige oth Digitalisierung UB Bayreuth application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=016498789&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Computational and structural approaches to drug discovery ligand-protein interactions Computer-Aided Design Drug Design Drug development Drugs Structure-activity relationships Ligands Ligands (Biochemistry) Protein engineering Proteins chemistry Ligand Biochemie (DE-588)4606532-5 gnd Arzneimittelentwicklung (DE-588)4143176-5 gnd Arzneimitteldesign (DE-588)4278218-1 gnd Proteindesign (DE-588)4346801-9 gnd |
| subject_GND | (DE-588)4606532-5 (DE-588)4143176-5 (DE-588)4278218-1 (DE-588)4346801-9 (DE-588)4173536-5 |
| title | Computational and structural approaches to drug discovery ligand-protein interactions |
| title_auth | Computational and structural approaches to drug discovery ligand-protein interactions |
| title_exact_search | Computational and structural approaches to drug discovery ligand-protein interactions |
| title_exact_search_txtP | Computational and structural approaches to drug discovery ligand-protein interactions |
| title_full | Computational and structural approaches to drug discovery ligand-protein interactions edited by Robert M. Stroud ... |
| title_fullStr | Computational and structural approaches to drug discovery ligand-protein interactions edited by Robert M. Stroud ... |
| title_full_unstemmed | Computational and structural approaches to drug discovery ligand-protein interactions edited by Robert M. Stroud ... |
| title_short | Computational and structural approaches to drug discovery |
| title_sort | computational and structural approaches to drug discovery ligand protein interactions |
| title_sub | ligand-protein interactions |
| topic | Computer-Aided Design Drug Design Drug development Drugs Structure-activity relationships Ligands Ligands (Biochemistry) Protein engineering Proteins chemistry Ligand Biochemie (DE-588)4606532-5 gnd Arzneimittelentwicklung (DE-588)4143176-5 gnd Arzneimitteldesign (DE-588)4278218-1 gnd Proteindesign (DE-588)4346801-9 gnd |
| topic_facet | Computer-Aided Design Drug Design Drug development Drugs Structure-activity relationships Ligands Ligands (Biochemistry) Protein engineering Proteins chemistry Ligand Biochemie Arzneimittelentwicklung Arzneimitteldesign Proteindesign Patentschrift |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=016498789&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT stroudrobert computationalandstructuralapproachestodrugdiscoveryligandproteininteractions |