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, eBook

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.

Zielgruppe

Research

Autoren/Hrsg.

Fernandez, Ariel

Inhaltsverzeichnis

Protein Cooperativity and Wrapping: Two Themes in the Transformative Platform of Molecular Targeted Therapy.- Wrapping Defects and the Architecture of Soluble Proteins.- Folding Cooperativity and the Wrapping of Intermediate States of Soluble Natural Proteins.- Wrapping Deficiencies and De-wetting Patterns in Soluble Proteins: A Blueprint for Drug Design.- Under-Wrapped Proteins in the Order–Disorder Twilight: Unraveling the Molecular Etiology of Aberrant Aggregation.- Evolution of Protein Wrapping and Implications for the Drug Designer.- Wrapping as a Selectivity Filter for Molecular Targeted Therapy: Preliminary Evidence.- Re-engineering an Anticancer Drug to Make It Safer: Modifying Imatinib to Curb Its Side Effects.- Wrapping Patterns as Universal Markers for Specificity in the Therapeutic Interference with Signaling Pathways.- Fulfilling a Therapeutic Imperative in Cancer Treatment: Control of Multi-target Drug Impact.- Inducing Folding By Crating the Target.- Wrapper Drugs as Therapeutic Editors of Side Effects.- Wrapper Drugs for Personalized Medicine.- Last Frontier and Back to the Drawing Board: Protein–Water Interfacial Tension in Drug Design.

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]."