Fernandez Transformative Concepts for Drug Design: Target Wrapping

1. Auflage 2010
ISBN: 978-3-642-11792-3
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 230 Seiten

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.

Autoren/Hrsg.

Fernandez, Ariel

Inhaltsverzeichnis

1;Preface;6
2;Contents;8
3;1 Protein Cooperativity and Wrapping: Two Themes in the Transformative Platform of Molecular Targeted Therapy;12
3.1;1.1 Many-Body Problems for the Drug Designer;12
3.2;1.2 Cooperative Protein Interactions: The Need for the Wrapping Concept;13
3.3;1.3 Poorly Wrapped Hydrogen Bonds are Promoters of Protein Associations;17
3.4;1.4 Wrapping Defects Are Sticky;20
3.5;1.5 Cooperative DrugTarget Associations: A Window into Molecular Engineering Possibilities;23
3.6;References;25
4;2 Wrapping Defects and the Architecture of Soluble Proteins;27
4.1;2.1 How Do Soluble Proteins Compensate for Their Wrapping Defects?;27
4.2;2.2 Thermodynamic Support for the Dehydron/Disulfide Balance Equation;32
4.3;2.3 Evolutionary Support for the Balance Equation;34
4.4;2.4 Wrapping Translates into Protein Architecture;34
4.5;References;36
5;3 Folding Cooperativity and the Wrapping of Intermediate States of Soluble Natural Proteins;37
5.1;3.1 Many-Body Picture of Protein Folding: Cooperativity and Wrapping;37
5.2;3.2 Hydrogen Bond Wrapping Requires Cooperative Folding;40
5.3;3.3 Generating Cooperative Folding Trajectories;42
5.4;3.4 Wrapping Patterns Along Folding Trajectories;47
5.5;3.5 Nanoscale Solvation Theory of Folding Cooperativity: Dynamic Benchmarks and Constant of Motion;51
5.6;3.6 Dehydronic Field Along the Folding Pathway and the Commitment to Fold;55
5.7;References;56
6;4 Wrapping Deficiencies and De-wetting Patterns in Soluble Proteins: A Blueprint for Drug Design;58
6.1;4.1 Hydration Defects in Soluble Proteins;58
6.2;4.2 Wrapping as a Marker of Local De-wetting Propensity;59
6.3;4.3 Dehydrons Are Loosely Hydrated;61
6.4;4.4 Displacing Loose Hydrating Molecules: A Blueprint for the Drug Designer;64
6.5;References;66
7;5 Under-Wrapped Proteins in the Order-Disorder Twilight: Unraveling the Molecular Etiology of Aberrant Aggregation;68
7.1;5.1 Dehydron Clusters and Disordered Regions;68
7.2;5.2 Discrete Solvent Effects Around Dehydrons;70
7.3;5.3 Dielectric Modulation of Interfacial Water Around Dehydrons;74
7.4;5.4 A Study Case: Dielectric Quenching in the p53 DNA-Binding Domain;76
7.5;5.5 Proteins with Dehydron Clusters;77
7.6;5.6 Misfolding and Aggregation: Consequences of a Massive Violation of Architectural Constraints;80
7.7;References;86
8;6 Evolution of Protein Wrapping and Implications for the Drug Designer;88
8.1;6.1 An Evolutionary Context for the Drug Designer;88
8.2;6.2 Wrapping Across Species: Hallmarks of Nonadaptive Traits in the Comparison of Orthologous Proteins;89
8.3;6.3 Wrapping and Natural Selection;91
8.4;6.4 How Do Humans Cope with Inefficient Selection?;93
8.4.1;6.4.1 Regulatory Patterns for Paralog Proteins;94
8.4.2;6.4.2 Wrapping Deficiency Causes Dosage Imbalance and Regulation Dissimilarity;96
8.5;6.5 Human Capacitance to Dosage Imbalances in the Concentrations of Under-Wrapped Proteins;102
8.6;6.6 Why Should the Drug Designer Be Mindful of Molecular Evolution?;102
8.7;References;104
9;7 Wrapping as a Selectivity Filter for Molecular Targeted Therapy: Preliminary Evidence;106
9.1;7.1 The Specificity Problem in Drug Design;106
9.2;7.2 Ligands as Wrappers of Proteins in PDB Complexes: Bioinformatics Evidence;112
9.3;7.3 Poor Dehydron Wrappers Make Poor Drugs;114
9.4;7.4 Wrapping as a Selectivity Filter;114
9.5;7.5 Wrapping as a Selectivity Filter: An Exercise in Drug Design;116
9.6;7.6 Wrapping-Based Selectivity Switch;120
9.7;References;122
10;8 Re-engineering an Anticancer Drug to Make It Safer: Modifying Imatinib to Curb Its Side Effects;125
10.1;8.1 Rational Control of Specificity: Toward a Safer Imatinib ;125
10.2;8.2 Unique De-wetting Hot Spots in the Target Protein Provide a Blueprint for Drug Design;126
10.3;8.3 In Silico Assays of the Water-Displacing Efficacy of a Wrapping Drug;133
10.4;8.4 High-Throughput Screening: Test-Tube Validation of the Engineered Specificity;133
10.5;8.5 In Vitro Assays: Selectively Modulating Imatinib Impact;135
10.6;8.6 In Vitro Assay of the Selective Anticancer Activity of the Wrapping Design;139
10.7;8.7 Enhanced Safety of the Wrapping Redesign in Animal Models of Gastrointestinal Stromal Tumor;140
10.8;8.8 Controlled Specificity Engineered Through Rational Design: Concluding Remarks;147
10.9;References;147
11;9 Wrapping Patterns as Universal Markers for Specificity in the Therapeutic Interference with Signaling Pathways;149
11.1;9.1 The Need for a Universal Selectivity Filter for Rationally Designed Kinase Inhibitors;149
11.2;9.2 Computational Tool Box for Comparative Analysis of Molecular Attributes Across the Human Kinome;151
11.2.1;9.2.1 Wrapping Inferences on Proteins with Unreported Structure;151
11.2.2;9.2.2 Alignment of Targetable Molecular Features Across the Human Kinome;152
11.3;9.3 Is Wrapping Pharmacologically Relevant? A Bioinformatics Analysis;152
11.4;9.4 A Target Library for the Human Kinome: Broadening the Technological Basis of Drug Discovery;160
11.5;9.5 Useful Annotations of a Library of Specificity-Promoting Target Features;161
11.6;9.6 The Dehydron Library as a Technological Resource;167
11.7;References;168
12;10 Fulfilling a Therapeutic Imperative in Cancer Treatment: Control of Multi-target Drug Impact;170
12.1;10.1 Is There Really a Case for Promiscuous Drugs in Anticancer Therapy?;170
12.2;10.2 Cleaning Dirty Drugs with Selectivity Filters: Basic Insights;172
12.3;10.3 Cleaning Dirty Drugs by Exploiting the Wrapping Filter: Proof of Concept;173
12.4;10.4 Cleaning Staurosporine Through a Wrapping Modification: A Stringent Test;180
12.5;10.5 Systems Biology Insights into Wrapping-Directed Design of Multi-target Kinase Inhibitors;184
12.6;10.6 Controlling the Cross-Reactivity of Sunitinib to Enhance Therapeutic Efficacy and Reduce Side Effects;186
12.7;10.7 Is a Paradigm Shift in Drug Discovery Imminent?;190
12.8;References;191
13;11 Inducing Folding By Crating the Target;194
13.1;11.1 Induced Folding: The Bte Noire of Drug Design;194
13.2;11.2 Wrapping the Target: A Tractable Case of Induced Folding;195
13.3;11.3 Kinase Inhibitors Designed to Crate Floppy Regions;197
13.4;11.4 Steering Induced Folding with High Specificity: The Emergence of the Crating Design Concept;201
13.5;References;202
14;12 Wrapper Drugs as Therapeutic Editors of Side Effects;204
14.1;12.1 The Editor Concept;204
14.2;12.2 Editing Drugs to Curb Side Effects;205
14.3;12.3 Designing a Therapeutic Editor Using the Wrapping Selectivity Filter;208
14.4;12.4 Therapeutic Editing: Toward a Proof of Principle;212
14.5;12.5 Future Perspectives for the Editing Therapy;215
14.6;References;216
15;13 Wrapper Drugs for Personalized Medicine;218
15.1;13.1 Wrapping as a Biomarker in Personalized Drug Therapy;218
15.2;13.2 Targeting Oncogenic Mutations with Wrapper Drugs;221
15.3;13.3 Closing Remarks;222
15.4;References;222
16;14 Last Frontier and Back to the Drawing Board: ProteinWater Interfacial Tension in Drug Design;223
16.1;14.1 Interfacial Tension Between Protein and Water: A Missing Chapter in Drug Design;223
16.2;14.2 Disrupting ProteinProtein Interfaces with Small Molecules;228
16.3;References;229
17;Epilogue;230
18;Index;232

Leseproben

"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]."