Transformative Concepts for Drug Design: Target Wrapping (eBook)

Ariel Fernandez (Autor)

eBook Download: PDF

2010 | 2010
X, 230 Seiten
Springer Berlin (Verlag)
978-3-642-11792-3 (ISBN)

Infos

In spite of the enticing promises of the post-genomic era, the pharmaceutical world is in a state of disarray. Drug discovery seems now riskier and more uncertain than ever. Thus, projects get routinely terminated in mid-stage clinical trials, new targets are getting harder to find, and successful therapeutic agents are often recalled as unanticipated side effects are discovered. Exploiting the huge output of genomic studies to make safer drugs has proven to be much more difficult than anticipated. More than ever, the lead in the pharmaceutical industry depends on the ability to harness innovative research, and this type of innovation can only come from one source: fundamental knowledge. This book squarely addresses this crucial problem since it introduces fundamental discoveries in basic biomolecular research that hold potential to broaden the technological base of the pharmaceutical industry. The book takes a fresh and fundamental look at the problem of how to design an effective drug with controlled specificity. Since the novel transformative concepts are unfamiliar to most practitioners, the first part of this book explains matters very carefully starting from a fairly elementary physico-chemical level. The second part of the book is devoted to practical applications, aiming at nothing less than a paradigm shift in drug design. This book is addressed to scientists working at the cutting edge of research in the pharmaceutical industry, but the material is at the same time accessible to senior undergraduates or graduate students interested in drug discovery and molecular design.

Inhalt

Preface 6
Contents 8
1 Protein Cooperativity and Wrapping: Two Themes in the Transformative Platform of Molecular Targeted Therapy 12
1.1 Many-Body Problems for the Drug Designer 12
1.2 Cooperative Protein Interactions: The Need for the Wrapping Concept 13
1.3 Poorly Wrapped Hydrogen Bonds are Promoters of Protein Associations 17
1.4 Wrapping Defects Are Sticky 20
1.5 Cooperative DrugTarget Associations: A Window into Molecular Engineering Possibilities 23
References 25
2 Wrapping Defects and the Architecture of Soluble Proteins 27
2.1 How Do Soluble Proteins Compensate for Their Wrapping Defects? 27
2.2 Thermodynamic Support for the Dehydron/Disulfide Balance Equation 32
2.3 Evolutionary Support for the Balance Equation 34
2.4 Wrapping Translates into Protein Architecture 34
References 36
3 Folding Cooperativity and the Wrapping of Intermediate States of Soluble Natural Proteins 37
3.1 Many-Body Picture of Protein Folding: Cooperativity and Wrapping 37
3.2 Hydrogen Bond Wrapping Requires Cooperative Folding 40
3.3 Generating Cooperative Folding Trajectories 42
3.4 Wrapping Patterns Along Folding Trajectories 47
3.5 Nanoscale Solvation Theory of Folding Cooperativity: Dynamic Benchmarks and Constant of Motion 51
3.6 Dehydronic Field Along the Folding Pathway and the Commitment to Fold 55
References 56
4 Wrapping Deficiencies and De-wetting Patterns in Soluble Proteins: A Blueprint for Drug Design 58
4.1 Hydration Defects in Soluble Proteins 58
4.2 Wrapping as a Marker of Local De-wetting Propensity 59
4.3 Dehydrons Are Loosely Hydrated 61
4.4 Displacing Loose Hydrating Molecules: A Blueprint for the Drug Designer 64
References 66
5 Under-Wrapped Proteins in the Order-Disorder Twilight: Unraveling the Molecular Etiology of Aberrant Aggregation 68
5.1 Dehydron Clusters and Disordered Regions 68
5.2 Discrete Solvent Effects Around Dehydrons 70
5.3 Dielectric Modulation of Interfacial Water Around Dehydrons 74
5.4 A Study Case: Dielectric Quenching in the p53 DNA-Binding Domain 76
5.5 Proteins with Dehydron Clusters 77
5.6 Misfolding and Aggregation: Consequences of a Massive Violation of Architectural Constraints 80
References 86
6 Evolution of Protein Wrapping and Implications for the Drug Designer 88
6.1 An Evolutionary Context for the Drug Designer 88
6.2 Wrapping Across Species: Hallmarks of Nonadaptive Traits in the Comparison of Orthologous Proteins 89
6.3 Wrapping and Natural Selection 91
6.4 How Do Humans Cope with Inefficient Selection? 93
6.4.1 Regulatory Patterns for Paralog Proteins 94
6.4.2 Wrapping Deficiency Causes Dosage Imbalance and Regulation Dissimilarity 96
6.5 Human Capacitance to Dosage Imbalances in the Concentrations of Under-Wrapped Proteins 102
6.6 Why Should the Drug Designer Be Mindful of Molecular Evolution? 102
References 104
7 Wrapping as a Selectivity Filter for Molecular Targeted Therapy: Preliminary Evidence 106
7.1 The Specificity Problem in Drug Design 106
7.2 Ligands as Wrappers of Proteins in PDB Complexes: Bioinformatics Evidence 112
7.3 Poor Dehydron Wrappers Make Poor Drugs 114
7.4 Wrapping as a Selectivity Filter 114
7.5 Wrapping as a Selectivity Filter: An Exercise in Drug Design 116
7.6 Wrapping-Based Selectivity Switch 120
References 122
8 Re-engineering an Anticancer Drug to Make It Safer: Modifying Imatinib to Curb Its Side Effects 125
8.1 Rational Control of Specificity: Toward a Safer Imatinib 125
8.2 Unique De-wetting Hot Spots in the Target Protein Provide a Blueprint for Drug Design 126
8.3 In Silico Assays of the Water-Displacing Efficacy of a Wrapping Drug 133
8.4 High-Throughput Screening: Test-Tube Validation of the Engineered Specificity 133
8.5 In Vitro Assays: Selectively Modulating Imatinib Impact 135
8.6 In Vitro Assay of the Selective Anticancer Activity of the Wrapping Design 139
8.7 Enhanced Safety of the Wrapping Redesign in Animal Models of Gastrointestinal Stromal Tumor 140
8.8 Controlled Specificity Engineered Through Rational Design: Concluding Remarks 147
References 147
9 Wrapping Patterns as Universal Markers for Specificity in the Therapeutic Interference with Signaling Pathways 149
9.1 The Need for a Universal Selectivity Filter for Rationally Designed Kinase Inhibitors 149
9.2 Computational Tool Box for Comparative Analysis of Molecular Attributes Across the Human Kinome 151
9.2.1 Wrapping Inferences on Proteins with Unreported Structure 151
9.2.2 Alignment of Targetable Molecular Features Across the Human Kinome 152
9.3 Is Wrapping Pharmacologically Relevant? A Bioinformatics Analysis 152
9.4 A Target Library for the Human Kinome: Broadening the Technological Basis of Drug Discovery 160
9.5 Useful Annotations of a Library of Specificity-Promoting Target Features 161
9.6 The Dehydron Library as a Technological Resource 167
References 168
10 Fulfilling a Therapeutic Imperative in Cancer Treatment: Control of Multi-target Drug Impact 170
10.1 Is There Really a Case for Promiscuous Drugs in Anticancer Therapy? 170
10.2 Cleaning Dirty Drugs with Selectivity Filters: Basic Insights 172
10.3 Cleaning Dirty Drugs by Exploiting the Wrapping Filter: Proof of Concept 173
10.4 Cleaning Staurosporine Through a Wrapping Modification: A Stringent Test 180
10.5 Systems Biology Insights into Wrapping-Directed Design of Multi-target Kinase Inhibitors 184
10.6 Controlling the Cross-Reactivity of Sunitinib to Enhance Therapeutic Efficacy and Reduce Side Effects 186
10.7 Is a Paradigm Shift in Drug Discovery Imminent? 190
References 191
11 Inducing Folding By Crating the Target 194
11.1 Induced Folding: The Bte Noire of Drug Design 194
11.2 Wrapping the Target: A Tractable Case of Induced Folding 195
11.3 Kinase Inhibitors Designed to Crate Floppy Regions 197
11.4 Steering Induced Folding with High Specificity: The Emergence of the Crating Design Concept 201
References 202
12 Wrapper Drugs as Therapeutic Editors of Side Effects 204
12.1 The Editor Concept 204
12.2 Editing Drugs to Curb Side Effects 205
12.3 Designing a Therapeutic Editor Using the Wrapping Selectivity Filter 208
12.4 Therapeutic Editing: Toward a Proof of Principle 212
12.5 Future Perspectives for the Editing Therapy 215
References 216
13 Wrapper Drugs for Personalized Medicine 218
13.1 Wrapping as a Biomarker in Personalized Drug Therapy 218
13.2 Targeting Oncogenic Mutations with Wrapper Drugs 221
13.3 Closing Remarks 222
References 222
14 Last Frontier and Back to the Drawing Board: ProteinWater Interfacial Tension in Drug Design 223
14.1 Interfacial Tension Between Protein and Water: A Missing Chapter in Drug Design 223
14.2 Disrupting ProteinProtein Interfaces with Small Molecules 228
References 229
Epilogue 230
Index 232

Textauszug

"Chapter 3 Folding Cooperativity and the Wrapping of Intermediate States of Soluble Natural Proteins (p.27-28)

This chapter focuses on the molecular basis of cooperativity as a means to understand the folding of soluble natural proteins. We explore the concept of protein wrapping, its intimate relation to cooperativity, and its bearing on the expediency of the folding process for natural proteins. As previously described, wrapping refers to the environmental modulation or protection of intramolecular electrostatic interactions through an exclusion of surrounding water that takes place as the chain folds onto itself.

Thus, a special many-body picture of the folding process is shown to emerge where the folding chain not only interacts with itself but also shapes the microenvironments that stabilize or destabilize the interactions. This picture reflects a competition between chain folding and backbone hydration leading to the prevalence of backbone hydrogen bonds for natural foldable proteins. A constant of motion governing the folding process emerges from the analysis.

3.1 Many-Body Picture of Protein Folding: Cooperativity and Wrapping

The physical underpinnings to the protein folding process remain elusive or, rather, difficult to cast in a useful form that enables structure prediction [1–10]. Thus, the possibility of inferring the folding pathway of a soluble protein solely from physical principles continues to elude major research efforts.

A major difficulty arises as we attempt to tackle this problem: as a peptide chain folds onto itself, it also shapes the microenvironments of the intramolecular interactions, and hence the strength and stability of such interactions need to be rescaled according to the extent to which they become “wrapped” or surrounded by other parts of the chain. Thus, interactions between different parts of the peptide chain not only entail the units directly engaged in the interaction but also the units involved in shaping their microenvironment, and the latter are just as important as they determine either the persistence or the ephemeral nature of such interactions.

This fact makes the folding problem essentially a many-body problem and points to the heart of cooperativity, a pivotal attribute of the folding process [4, 6]. Furthermore, it highlights the intimate link between cooperativity and wrapping: intramolecular hydrogen bonds prevail only if properly wrapped and this requires a cooperative process.

To further explore the molecular basis of cooperativity, we need to examine the folding process from a physico-chemical perspective: With an amide and carbonyl group per residue, the backbone of the protein chain is highly polar and this molecular property imposes severe constraints on the nature of the hydrophobic collapse and on the chain composition of proteins capable of sustaining such a collapse [2, 9, 11].

Thus, the hydrophobic collapse entails the dehydration of backbone amides and carbonyls and such a process would be thermodynamically disfavored if it were not for the possibility of amides and carbonyls to engage in hydrogen bonding with each other. Hence, not every hydrophobic collapse qualifies as being conducive to folding the protein chain: Only a collapse that ensures the formation and protection of backbone hydrogen bonds is likely to ensure an expedient folding of the chain [2]."

Produkt-Details

• Erscheint lt. Verlag: 28.4.2010
• Zusatzinfo: X, 230 p.
• Verlagsort: Berlin
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie
• Themenwelt: Naturwissenschaften ► Biologie
• Themenwelt: Naturwissenschaften ► Chemie
• Themenwelt: Technik
• Schlagworte: Base • Biophysics • Cancer Treatment • Chemistry • clinical trial • drug design • drug discovery • Kinases • medicinal chemistry • Medicine • molecular biophysics • Molecular Cancer Therapy • Protein • Protein Structure • targeted therapy • target wrapping • Textbook • Translation
• ISBN-10: 3-642-11792-9 / 3642117929
• ISBN-13: 978-3-642-11792-3 / 9783642117923