مورد إلكتروني
A Bioinorganic Approach to Fragment-Based Drug Discovery Targeting Metalloenzymes.
| العنوان: | A Bioinorganic Approach to Fragment-Based Drug Discovery Targeting Metalloenzymes. |
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| المؤلفون: | Cohen, Seth M |
| المصدر: | Accounts of chemical research; vol 50, iss 8, 2007-2016; 0001-4842 |
| بيانات النشر: | eScholarship, University of California 2017-08-01 |
| تفاصيل مُضافة: | Cohen, Seth M |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | Metal-dependent enzymes (i.e., metalloenzymes) make up a large fraction of all enzymes and are critically important in a wide range of biological processes, including DNA modification, protein homeostasis, antibiotic resistance, and many others. Consequently, metalloenzymes represent a vast and largely untapped space for drug development. The discovery of effective therapeutics that target metalloenzymes lies squarely at the interface of bioinorganic and medicinal chemistry and requires expertise, methods, and strategies from both fields to mount an effective campaign. In this Account, our research program that brings together the principles and methods of bioinorganic and medicinal chemistry are described, in an effort to bridge the gap between these fields and address an important class of medicinal targets. Fragment-based drug discovery (FBDD) is an important drug discovery approach that is particularly well suited for metalloenzyme inhibitor development. FBDD uses relatively small but diverse chemical structures that allow for the assembly of privileged molecular collections that focus on a specific feature of the target enzyme. For metalloenzyme inhibition, the specific feature is rather obvious, namely, a metal-dependent active site. Surprisingly, prior to our work, the exploration of diverse molecular fragments for binding the metal active sites of metalloenzymes was largely unexplored. By assembling a modest library of metal-binding pharmacophores (MBPs), we have been able to find lead hits for many metalloenzymes and, from these hits, develop inhibitors that act via novel mechanisms of action. A specific case study on the use of this strategy to identify a first-in-class inhibitor of zinc-dependent Rpn11 (a component of the proteasome) is highlighted. The application of FBDD for the development of metalloenzyme inhibitors has raised several other compelling questions, such as how the metalloenzyme active site influences the coordination chemistry of bound f |
| مصطلحات الفهرس: | Enzymes, Metalloproteins, Drug Delivery Systems, Drug Design, Drug Discovery, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Chemical Sciences, General Chemistry, article |
| URL: | |
| الإتاحة: | Open access content. Open access content public |
| ملاحظة: | application/pdf Accounts of chemical research vol 50, iss 8, 2007-2016 0001-4842 |
| أرقام أخرى: | CDLER oai:escholarship.org:ark:/13030/qt5dm5z305 qt5dm5z305 https://escholarship.org/uc/item/5dm5z305Test https://escholarship.orgTest/ 1391613310 |
| المصدر المساهم: | UC MASS DIGITIZATION From OAIster®, provided by the OCLC Cooperative. |
| رقم الانضمام: | edsoai.on1391613310 |
| قاعدة البيانات: | OAIster |
| الوصف غير متاح. |