Design and Synthesis of Small-molecule Protein-protein Interaction Antagonists PDF Download
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Author: Xu Han
Publisher:
ISBN:
Category : Calcium channels
Languages : en
Pages : 276
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Book Description
Protein-protein interactions play a crucial role in a wide range of biological processes. Research on the design and synthesis of small molecules to modulate these proteinprotein interactions can lead to new targets and drugs to modulate their function. In chapter one, we discuss the design and synthesis of small molecules to probe a proteinprotein interaction in a voltage-gated Ca2+ channel. Virtual screening identified a compound (BTT-3) that contained a 3,4-dihydro-3,4'-pyrazole core. This compound had modest biological activity when tested in a fluorescence polarization (FP) assay. The synthetic route to BTT-3 consisted of six steps. In addition, analogs of BTT-3 were made for a structure-activity study to establish the importance of a carboxylate moiety. We also synthesized a biotinylated benzophenone photo-affinity probe and linked it to BTT-3 to identify additional protein targets of the compound. In Chapter two, small-molecule antagonists targeting uPA-uPAR protein-protein interaction are presented. A total of 500 commercially-available compounds were previously identified by virtual screening and tested by a FP assay. Three classes of compounds were found with biological activity. The first class of compounds contains pyrrolidone core structures represented by IPR- 1110, the second class has a novel pyrrolo[3,4-c]pyrazole ring system, represented by xv IPR-1283 and the last series had compounds with a 1,2-disubstituted 1,2- dihydropyrrolo[3,4-b]indol-3(4H)-one core structure, represented by IPR-540. Each of these three compounds were synthesized and assessed by FP and ELISA assays. A binding mode of IPR-1110 with uPA was subsequently proposed. Based on this binding mode, another 61 IPR-1110 derivatives were synthesized by us to illustrate the SAR activity. Analogs of the other two series were also synthesized.
Author: Xu Han
Publisher:
ISBN:
Category : Calcium channels
Languages : en
Pages : 276
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Book Description
Protein-protein interactions play a crucial role in a wide range of biological processes. Research on the design and synthesis of small molecules to modulate these proteinprotein interactions can lead to new targets and drugs to modulate their function. In chapter one, we discuss the design and synthesis of small molecules to probe a proteinprotein interaction in a voltage-gated Ca2+ channel. Virtual screening identified a compound (BTT-3) that contained a 3,4-dihydro-3,4'-pyrazole core. This compound had modest biological activity when tested in a fluorescence polarization (FP) assay. The synthetic route to BTT-3 consisted of six steps. In addition, analogs of BTT-3 were made for a structure-activity study to establish the importance of a carboxylate moiety. We also synthesized a biotinylated benzophenone photo-affinity probe and linked it to BTT-3 to identify additional protein targets of the compound. In Chapter two, small-molecule antagonists targeting uPA-uPAR protein-protein interaction are presented. A total of 500 commercially-available compounds were previously identified by virtual screening and tested by a FP assay. Three classes of compounds were found with biological activity. The first class of compounds contains pyrrolidone core structures represented by IPR- 1110, the second class has a novel pyrrolo[3,4-c]pyrazole ring system, represented by xv IPR-1283 and the last series had compounds with a 1,2-disubstituted 1,2- dihydropyrrolo[3,4-b]indol-3(4H)-one core structure, represented by IPR-540. Each of these three compounds were synthesized and assessed by FP and ELISA assays. A binding mode of IPR-1110 with uPA was subsequently proposed. Based on this binding mode, another 61 IPR-1110 derivatives were synthesized by us to illustrate the SAR activity. Analogs of the other two series were also synthesized.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
Author: Herbert Waldmann
Publisher: Springer Science & Business Media
ISBN: 3662053144
Category : Medical
Languages : en
Pages : 248
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Book Description
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: Justin Thomas Ernst
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
Author: Alexander Dömling
Publisher: John Wiley & Sons
ISBN: 3527648224
Category : Medical
Languages : en
Pages : 493
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Book Description
Treating protein-protein interactions as a novel and highly promising class of drug targets, this volume introduces the underlying strategies step by step, from the biology of PPIs to biophysical and computational methods for their investigation. The main part of the book describes examples of protein targets for which small molecule modulators have been developed, covering such diverse fields as cancer, autoimmune disorders and infectious diseases. Tailor-made for the practicing medicinal chemist, this ready reference includes a wide selection of case studies taken straight from the development pipeline of major pharmaceutical companies to illustrate the power and potential of this approach. From the contents: * Prediction of intra- and inter-species protein-protein interactions facilitating systems biology studies * Modulators of protein-protein interactions: The importance of Three-Dimensionality * Interactive technologies for leveraging the known chemistry of anchor residues * SH3 Domains as Drug Targets * P53 MDM2 Antagonists: Towards Non Genotoxic Anticancer Treatments * Inhibition of LFA-1/ICAM interaction for treatment of autoimmune diseases * The PIF-binding pocket of AGC kinases * Peptidic inhibitors of protein-protein interactions for cell adhesion receptors * The REPLACE Strategy for generating Non-ATP competitive Inhibitors of Cell-Cycle Protein Kinases and more
Author: Ernest Giralt
Publisher: John Wiley & Sons
ISBN: 1119957214
Category : Science
Languages : en
Pages : 296
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Book Description
A new perspective on the design of molecular therapeutics is emerging. This new strategy emphasizes the rational complementation of functionality along extended patches of a protein surface with the aim of inhibiting protein/protein interactions. The successful development of compounds able to inhibit these interactions offers a unique chance to selectively intervene in a large number of key cellular processes related to human disease. Protein Surface Recognition presents a detailed treatment of this strategy, with topics including: an extended survey of protein-protein interactions that are key players in human disease and biology and the potential for therapeutics derived from this new perspective the fundamental physical issues that surround protein-protein interactions that must be considered when designing ligands for protein surfaces examples of protein surface-small molecule interactions, including treatments of protein-natural product interactions, protein-interface peptides, and rational approaches to protein surface recognition from model to biological systems a survey of techniques that will be integral to the discovery of new small molecule protein surface binders, from high throughput synthesis and screening techniques to in silico and in vitro methods for the discovery of novel protein ligands. Protein Surface Recognition provides an intellectual “tool-kit” for investigators in medicinal and bioorganic chemistry looking to exploit this emerging paradigm in drug discovery.
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Author: Justin Thomas Ernst
Publisher:
ISBN:
Category :
Languages : en
Pages : 460
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Book Description
Author: Ali Tavassoli
Publisher: Royal Society of Chemistry
ISBN: 178801569X
Category : Science
Languages : en
Pages : 357
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Book Description
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: Logan Reid Hoggard
Publisher:
ISBN:
Category : Chemical inhibitors
Languages : en
Pages : 113
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Book Description
Author: Hiroyuki Osada
Publisher: John Wiley & Sons
ISBN: 0470495006
Category : Science
Languages : en
Pages : 310
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Book Description
Discover the link between the latest chemical biology approaches and novel drug therapies! Protein Targeting with Small Molecules: Chemical Biology Techniques and Applications takes readers beyond the use of chemical biology in basic research, providing a highly relevant look at techniques that can address the challenges of biology and drug design and development. This indispensable bench companion features up-to-date coverage of advances in chemistry and assesses their impact on developing new therapeutics, making it ideal for chemical biologists and medicinal chemists who are developing small molecule drugs to target proteins and treat diseases. In addition, the book examines the full range of complex biological systems and their interrelationship with chemistry, from the interaction of biological response modifiers with proteins to the chemical biology of cell surface oligosaccharides. Distinguished by an overview of chemical biology that is reinforced and clarified by detailed examples and descriptions of techniques, Protein Targeting with Small Molecules: Chemical Biology Techniques and Applications: Introduces key technologies and methods of chemical biology designed to detect the interactions of small molecules and proteins Facilitates the discovery of small molecules that bind to proteins and describes the molecules' application in the investigation of biological processes Presents timely coverage of the development of fluorescent probes for small molecules, as well as the generation of small molecule ligands and inhibitors Reviews important techniques such as chemical genomics, target profiling, immobilization technology, detection methods, chemical inhibition, and structure-based targeting Offers a compelling synopsis of data that underscores the recent progress made in the area of targeting proteins by small molecules
