Biochemical Characterization of Small-molecule Inhibitors of Protein-protein Interactions PDF Download

Author: Stefan Rubner
Publisher:
ISBN:
Category :
Languages : de
Pages :

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Author: Sabine Schubert
Publisher:
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Category :
Languages : de
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Author: Djamali Muhoza
Publisher:
ISBN:
Category :
Languages : en
Pages : 250

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The Ras superfamily of GTPases has 167 proteins that are involved in various cellular processes such as proliferation, transformation, migration, and inhibition of cell death. Mutations, abnormal expression, and function of these proteins are observed in many diseases, including several forms of cancer. Even though these GTPases were among the first discovered oncogenes, no successful Ras drug candidate has successfully passed clinical trials. Drugs targeting these proteins have failed mainly because of the complexity of their regulation, their high affinity to GTP, and their structure's dynamic nature. Recently, novel promising targeting approaches have renewed interest in the Ras drug discovery field. One such approach uses small molecules to bind to small pockets on the protein rendering it unable to operate and bind to effectors. In this study, inhibition of Cdc42, a Ras-related GTPase in the Rho subfamily, was investigated. Using various computational, biophysical, and biochemical assays, we characterized the binding of a novel inhibitor to Cdc42. The effects of this inhibitor to Cdc42 protein-protein interactions (PPIs) were also investigated. Results show that the small molecule binds and stabilizes Cdc42 making it more resistant to denaturation. It also affects the protein's hydrolysis activity and binding to PAK1, a crucial Cdc42 effector. A method to efficiently isolate and purify a PAK1 derived peptide was also developed. The results from these experiments show that ZCL278 is an effective Cdc42 inhibitor. However, the low effects of this inhibitor and low solubility in water make it a less attractive drug candidate. Using the results from this study, more soluble, ZCL278-like small molecules with better drug parameters are presented here as potential Cdc42 inhibitors. These small molecules will serve as candidates for investigating and developing better inhibitors of Cdc42-induced abnormal cell signaling.

Author: Herbert Waldmann
Publisher: Springer Science & Business Media
ISBN: 3662053144
Category : Medical
Languages : en
Pages : 248

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Based on the international workshop on 'Small Molecule - Protein Interactions' held in Berlin, April 24-26, 2002, researchers from industry and academic laboratories describe novel and efficient ways selecting promising new drug targets and developing small molecule inhibitors against them. The structure of the book corresponds to the different aspects of the drug discovery process. All chapters are written by leading experts in the field, who present and discuss the most recent state-of-the-art tools and techniques for the development of novel drugs. The value of the book lies in surveying and summarizing the approaches taken by different companies and institutions giving the reader a balanced view on the use of the latest techniques on the one hand and experience-based assistance in selecting appropriate tools for their own work on the other hand.

Author: Ali Tavassoli
Publisher: Royal Society of Chemistry
ISBN: 178801569X
Category : Science
Languages : en
Pages : 357

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Protein-protein interactions (PPI) are at the heart of the majority of cellular processes, and are frequently dysregulated or usurped in disease. Given this central role, the inhibition of PPIs has been of significant interest as a means of treating a wide variety of diseases. However, there are inherent challenges in developing molecules capable of disrupting the relatively featureless and large interfacial areas involved. Despite this, there have been a number of successes in this field in recent years using both traditional drug discovery approaches and innovative, interdisciplinary strategies using novel chemical scaffolds. This book comprehensively covers the various aspects of PPI inhibition, encompassing small molecules, peptidomimetics, cyclic peptides, stapled peptides and macrocycles. Illustrated throughout with successful case studies, this book provides a holistic, cutting-edge view of the subject area and is ideal for chemical biologists and medicinal chemists interested in developing PPI inhibitors.

Author: Lyubomir Vassilev
Publisher: Springer Science & Business Media
ISBN: 3642170838
Category : Medical
Languages : en
Pages : 180

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In this volume, the editors have collected the knowledgeable insights of a number of leaders in this field - researchers who have achieved success in addressing the difficult problem of inhibiting protein-protein interactions. These researchers describe their unique approaches, and share experiences, results, thoughts, and opinions. The content of the articles is rich, and in terms of scope ranges from generalized approaches to specific case studies. There are various focal points, including methodologies and the molecules themselves. Ultimately, there are numerous lessons to be taken away from this collection, and the editors hope that this snapshot of the current state of the art in developing protein-protein inhibitors not only pays tribute to the past successes, but also generates excitement about the future potential of this field

Author: Jean-Paul Renaud
Publisher: John Wiley & Sons
ISBN: 1118900502
Category : Medical
Languages : en
Pages : 1367

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With the most comprehensive and up-to-date overview of structure-based drug discovery covering both experimental and computational approaches, Structural Biology in Drug Discovery: Methods, Techniques, and Practices describes principles, methods, applications, and emerging paradigms of structural biology as a tool for more efficient drug development. Coverage includes successful examples, academic and industry insights, novel concepts, and advances in a rapidly evolving field. The combined chapters, by authors writing from the frontlines of structural biology and drug discovery, give readers a valuable reference and resource that: Presents the benefits, limitations, and potentiality of major techniques in the field such as X-ray crystallography, NMR, neutron crystallography, cryo-EM, mass spectrometry and other biophysical techniques, and computational structural biology Includes detailed chapters on druggability, allostery, complementary use of thermodynamic and kinetic information, and powerful approaches such as structural chemogenomics and fragment-based drug design Emphasizes the need for the in-depth biophysical characterization of protein targets as well as of therapeutic proteins, and for a thorough quality assessment of experimental structures Illustrates advances in the field of established therapeutic targets like kinases, serine proteinases, GPCRs, and epigenetic proteins, and of more challenging ones like protein-protein interactions and intrinsically disordered proteins

Author: Martin Zacharias
Publisher: World Scientific
ISBN: 184816338X
Category : Science
Languages : en
Pages : 401

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Given the immense progress achieved in elucidating protein-protein complex structures and in the field of protein interaction modeling, there is great demand for a book that gives interested researchers/students a comprehensive overview of the field. This book does just that. It focuses on what can be learned about protein-protein interactions from the analysis of protein-protein complex structures and interfaces. What are the driving forces for protein-protein association? How can we extract the mechanism of specific recognition from studying protein-protein interfaces? How can this knowledge be used to predict and design protein-protein interactions (interaction regions and complex structures)? What methods are currently employed to design protein-protein interactions, and how can we influence protein-protein interactions by mutagenesis and small-molecule drugs or peptide mimetics?The book consists of about 15 review chapters, written by experts, on the characterization of protein-protein interfaces, structure determination of protein complexes (by NMR and X-ray), theory of protein-protein binding, dynamics of protein interfaces, bioinformatics methods to predict interaction regions, and prediction of protein-protein complex structures (docking and homology modeling of complexes, etc.) and design of protein-protein interactions. It serves as a bridge between studying/analyzing protein-protein complex structures (interfaces), predicting interactions, and influencing/designing interactions.

Author: Hans-Joachim Böhm
Publisher: John Wiley & Sons
ISBN: 3527605517
Category : Science
Languages : en
Pages : 262

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The lock-and-key principle formulated by Emil Fischer as early as the end of the 19th century has still not lost any of its significance for the life sciences. The basic aspects of ligand-protein interaction may be summarized under the term 'molecular recognition' and concern the specificity as well as stability of ligand binding. Molecular recognition is thus a central topic in the development of active substances, since stability and specificity determine whether a substance can be used as a drug. Nowadays, computer-aided prediction and intelligent molecular design make a large contribution to the constant search for, e. g., improved enzyme inhibitors, and new concepts such as that of pharmacophores are being developed. An up-to-date presentation of an eternally young topic, this book is an indispensable information source for chemists, biochemists and pharmacologists dealing with the binding of ligands to proteins.

Author: Timothy D. Veenstra
Publisher: John Wiley & Sons
ISBN: 0470007737
Category : Science
Languages : en
Pages : 361

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Written by recognized experts in the study of proteins, Proteomics for Biological Discovery begins by discussing the emergence of proteomics from genome sequencing projects and a summary of potential answers to be gained from proteome-level research. The tools of proteomics, from conventional to novel techniques, are then dealt with in terms of underlying concepts, limitations and future directions. An invaluable source of information, this title also provides a thorough overview of the current developments in post-translational modification studies, structural proteomics, biochemical proteomics, microfabrication, applied proteomics, and bioinformatics relevant to proteomics. Presents a comprehensive and coherent review of the major issues faced in terms of technology development, bioinformatics, strategic approaches, and applications Chapters offer a rigorous overview with summary of limitations, emerging approaches, questions, and realistic future industry and basic science applications Discusses higher level integrative aspects, including technical challenges and applications for drug discovery Accessible to the novice while providing experienced investigators essential information Proteomics for Biological Discovery is an essential resource for students, postdoctoral fellows, and researchers across all fields of biomedical research, including biochemistry, protein chemistry, molecular genetics, cell/developmental biology, and bioinformatics.