Abstract
Finding novel compounds as starting points for optimization is a major challenge in drug discovery research. Fragment-based methods have emerged in the past ten years as an effective way to sample chemical diversity with a limited number of low molecular weight compounds. The structures of the fragments(s) binding to the protein can then be used to design new compounds with increased affinity, specificity and novelty. This article describes the Vernalis approach to fragment based drug discovery, called SeeDs (Structural exploitation of experimental Drug startpoints). The approach includes the design of a fragment library, identification of fragments that bind competitively to a target by ligand-based NMR techniques and protein crystal structures to characterize binding. Fragments that bind are then evolved to hits, either by growing the fragment or by combining structural features from a number of compounds. The process is illustrated with examples from recent medicinal chemistry programmes to discover compounds against the oncology targets Hsp90 and PDK1. In addition, we summarise our experience with using molecular docking calculations to predict fragment binding and anecdotes on the selectivity and binding modes for fragments seen against a range of targets.
Keywords: Structure-based drug discovery, fragment-based drug discovery, drug design, NMR spectroscopy, Hsp90, PDK1
Current Topics in Medicinal Chemistry
Title: The SeeDs Approach: Integrating Fragments into Drug Discovery
Volume: 7 Issue: 16
Author(s): Roderick E. Hubbard, Ben Davis, Ijen Chen and Martin J. Drysdale
Affiliation:
Keywords: Structure-based drug discovery, fragment-based drug discovery, drug design, NMR spectroscopy, Hsp90, PDK1
Abstract: Finding novel compounds as starting points for optimization is a major challenge in drug discovery research. Fragment-based methods have emerged in the past ten years as an effective way to sample chemical diversity with a limited number of low molecular weight compounds. The structures of the fragments(s) binding to the protein can then be used to design new compounds with increased affinity, specificity and novelty. This article describes the Vernalis approach to fragment based drug discovery, called SeeDs (Structural exploitation of experimental Drug startpoints). The approach includes the design of a fragment library, identification of fragments that bind competitively to a target by ligand-based NMR techniques and protein crystal structures to characterize binding. Fragments that bind are then evolved to hits, either by growing the fragment or by combining structural features from a number of compounds. The process is illustrated with examples from recent medicinal chemistry programmes to discover compounds against the oncology targets Hsp90 and PDK1. In addition, we summarise our experience with using molecular docking calculations to predict fragment binding and anecdotes on the selectivity and binding modes for fragments seen against a range of targets.
Export Options
About this article
Cite this article as:
Hubbard E. Roderick, Davis Ben, Chen Ijen and Drysdale J. Martin, The SeeDs Approach: Integrating Fragments into Drug Discovery, Current Topics in Medicinal Chemistry 2007; 7 (16) . https://dx.doi.org/10.2174/156802607782341109
DOI https://dx.doi.org/10.2174/156802607782341109 |
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
-
Nucleic Acid Aptamers Against Proteases
Current Medicinal Chemistry A Review on Repurposed Drugs and Vaccine Trials for Combating SARS CoV-2
Current Drug Research Reviews The Role of Halogen Bonding in Inhibitor Recognition and Binding by Protein Kinases
Current Topics in Medicinal Chemistry The Current Status of the NNRTI Family of Antiretrovirals Used Against HIV Infection
Current Medicinal Chemistry Substituted 3-R-2,8-Dioxo-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4] triazino [2,3-c]quinazoline-5a(6H)carboxylic Acids and their Salts – a Promising Class of Anti-inflammatory Agents
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry The Use of Conformational Restriction in Medicinal Chemistry
Current Topics in Medicinal Chemistry A Review on Development and Characterization of a Cost-effective Targeted Quality-driven Antimalarial Product with an Emphasis on Phytosomes
Current Drug Targets Recent Advances in Antiangiogenic Agents with VEGFR as Target
Mini-Reviews in Medicinal Chemistry A Review on Remdesivir: A Broad-spectrum Antiviral Molecule for Possible COVID-19 Treatment
Mini-Reviews in Medicinal Chemistry Molecular Mechanism and Targets of the Antimicrobial Activity of Metal Nanoparticles
Current Topics in Medicinal Chemistry Targeting the Multidrug ABCG2 Transporter with Flavonoidic Inhibitors: In Vitro Optimization and In Vivo Validation
Current Medicinal Chemistry Oxidative Stress and Neurodegenerative Diseases: Looking for a Therapeutic Solution Inspired on Benzopyran Chemistry
Current Topics in Medicinal Chemistry Synthesis of Drugs and Biorelevant N-heterocycles Employing Recent Advances in C-N Bond Formation
Current Organic Chemistry Persons with Co-Existing Neurological Disorders: Risk Analysis, Considerations and Management in COVID-19 Pandemic
CNS & Neurological Disorders - Drug Targets Advanced Pharmacophore Model of Non-Competitive AMPA Antagonist 2,3-benzodiazepines
Letters in Drug Design & Discovery Coumarins as Inhibitors of HIV Reverse Transcriptase
Current HIV Research Potential Applications of <i>Sarcopoterium Spinosum</i> as Medicinal Plants: Overview and Future Trends
Current Traditional Medicine Protein Aggregation and Defective RNA Metabolism as Mechanisms for Motor Neuron Damage
CNS & Neurological Disorders - Drug Targets Infection, Infectious Agents and Vascular Disease
Reviews on Recent Clinical Trials Otitis Media: Epidemiology and Management
Infectious Disorders - Drug Targets