Abstract
Using localized NMR spectroscopy on immobilized targets provides us with a method to simultaneously assess binding of small molecules to two different samples. This Target Immobilized NMR Screening (TINS) has a number of advantages, not least is the requirement for minimal quantities of non-isotopically labeled protein and the applicability to insoluble or unstable targets. The technique is sensitive to binding with KD values in the range of 100 nM to 20 mM, while careful selection of the reference protein reduces the number of false positive hits. This combination ensures a maximal number of valid hits from which to select starting points for hit elaboration projects. Hits can be prioritized using biological assays when appropriate, as well as an array of biophysical techniques. So far a variety of soluble proteins, including kinases, GTPases, viral targets and proteases, as well as a membrane protein, have been successfully screened against our fragment library. Here we illustrate our experiences with a number of examples which emphasize the usefulness of the method in selecting and prioritizing fragment hits for elaboration towards leads.
Keywords: Fragment Screening, NMR, protein immobilization, hit validation
Current Topics in Medicinal Chemistry
Title: Target Immobilization and NMR Screening of Fragments in Early Drug Discovery
Volume: 9 Issue: 18
Author(s): Gregg Siegal and Johan G. Hollander
Affiliation:
Keywords: Fragment Screening, NMR, protein immobilization, hit validation
Abstract: Using localized NMR spectroscopy on immobilized targets provides us with a method to simultaneously assess binding of small molecules to two different samples. This Target Immobilized NMR Screening (TINS) has a number of advantages, not least is the requirement for minimal quantities of non-isotopically labeled protein and the applicability to insoluble or unstable targets. The technique is sensitive to binding with KD values in the range of 100 nM to 20 mM, while careful selection of the reference protein reduces the number of false positive hits. This combination ensures a maximal number of valid hits from which to select starting points for hit elaboration projects. Hits can be prioritized using biological assays when appropriate, as well as an array of biophysical techniques. So far a variety of soluble proteins, including kinases, GTPases, viral targets and proteases, as well as a membrane protein, have been successfully screened against our fragment library. Here we illustrate our experiences with a number of examples which emphasize the usefulness of the method in selecting and prioritizing fragment hits for elaboration towards leads.
Export Options
About this article
Cite this article as:
Siegal Gregg and Hollander G. Johan, Target Immobilization and NMR Screening of Fragments in Early Drug Discovery, Current Topics in Medicinal Chemistry 2009; 9 (18) . https://dx.doi.org/10.2174/156802609790102400
DOI https://dx.doi.org/10.2174/156802609790102400 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Matrix Metalloproteinases in Respiratory Diseases: From Pathogenesis to Potential Clinical Implications
Current Medicinal Chemistry Synthesis of A/B-Ring Partial Analogs of Bruceantin as Potential Antimalarial Agents
Medicinal Chemistry Synthesis and Antimalarial Activity of Novel Side Chain Modified Antimalarial Agents Derived from 4-Aminoquinoline
Medicinal Chemistry Prognostic Significance of Risk Factors and Biomarkers in Patients Hospitalized for Cardiorenal Syndromes: A Pilot Study
Current Medicinal Chemistry Anticonvulsant and Antinociceptive Actions of Novel Adenosine Kinase Inhibitors
Current Topics in Medicinal Chemistry Antipsoriatic Drug Development: Challenges and New Emerging Therapies
Recent Patents on Inflammation & Allergy Drug Discovery Synthesis and Biological Activities of New Halophenols
Medicinal Chemistry Antiprotozoal Agents: An Overview
Anti-Infective Agents in Medicinal Chemistry Hematoxylin as a General and Efficient Ligand for the Cu(I)-catalyzed S-arylation of Thiols with Aryl Halides in DMF-H2O
Letters in Organic Chemistry Recent Advances in the Development of Small-molecule CCR5 Inhibitors for HIV
Mini-Reviews in Medicinal Chemistry A New Multicomponent Reaction MCR4 for the Synthesis of Analogs of Staurosporine
Current Organic Chemistry subject Index To Volume 2
Mini-Reviews in Medicinal Chemistry Forecasting of COVID-19 Cases in India: A Predictive Study
Current Immunology Reviews (Discontinued) Acknowledgements to Reviewers:
Current Rheumatology Reviews Purine Derivatives as Ligands for A3 Adenosine Receptors
Current Topics in Medicinal Chemistry Targeting Bacterial RNA Polymerase: Promises for Future Antisense Antibiotics Development
Infectious Disorders - Drug Targets Recent Developments in Oxidative Processes in Steroid Chemistry
Current Organic Chemistry Repositioning of Drugs as a Promising Strategy to Fight COVID-19
Coronaviruses Challenges in the Discovery and Optimization of mGlu2/4 Heterodimer Positive Allosteric Modulators
Letters in Drug Design & Discovery Glutamine, Glucose and other Fuels for Cancer
Current Pharmaceutical Design