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
-
Recent Advances of MEK Inhibitors and Their Clinical Progress
Current Topics in Medicinal Chemistry How Large Does a Compound Screening Collection Need To Be?
Combinatorial Chemistry & High Throughput Screening Enzyme Inhibitors
Current Bioactive Compounds Photocatalysis and Virus. From Theory to Applications
Journal of Photocatalysis Current Advances and Prospects in Carbon Nanomaterials-based Drug Deliver Systems for Cancer Therapy
Current Medicinal Chemistry Synthesis, β -catenin Translocation Capability and ALP Activation Activity of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one Derivatives
Medicinal Chemistry Quaternary Structure, Substrate Selectivity and Inhibitor Design for SARS 3C-Like Proteinase
Current Pharmaceutical Design Synthesis and Biological Evaluation of Pyrazolo[3,4-<i>b</i>]pyridin-4-ones as a New Class of Topoisomerase II Inhibitors
Medicinal Chemistry Biological Importance, Therapeutic Benefit and Analytical Aspects of Bioactive Flavonoid Pectolinarin in the Nature
Drug Metabolism Letters 1,3,4-Oxadiazole Derivatives as Potential Biological Agents
Mini-Reviews in Medicinal Chemistry A Meta-Analysis of Safety of Different Regimens of Remdesivir in COVID-19 Patients
Current Drug Safety Outlining the Molecules Tested <i>In Vivo</i> for Chagas Disease, Malaria, and Schistosomiasis Over the Last Six Years - A Literature Review Focused on New Synthetic Drug Identities and Repurposing Strategies
Current Medicinal Chemistry Triazole-linked Chalcone and Flavone Hybrid Compounds Based on AZT Exhibiting In Vitro Anti-Cancer Activity
Letters in Drug Design & Discovery Aqueous Drug Solubility: What Do We Measure, Calculate and QSPR Predict?
Mini-Reviews in Medicinal Chemistry Recent Developments in the Synthesis of Novel Aminoglycoside Antibiotics
Anti-Infective Agents in Medicinal Chemistry Evolution of Peptide-Based Prostate-Specific Membrane Antigen (PSMA) Inhibitors: An Approach to Novel Prostate Cancer Therapeutics
Current Medicinal Chemistry SAR Modeling: Effect of Experimental Ambiguity
Combinatorial Chemistry & High Throughput Screening Beyond B-Cell Epitopes: Curating Positive Data on Antipeptide Paratope Binding to Support Peptide-Based Vaccine Design
Protein & Peptide Letters Need for Nutritious Convenience Foods for the Elderly Population: A Review
Current Nutrition & Food Science Imaging Features of Thoracic Manifestations of Behçet’s Disease: Beyond Pulmonary Artery Involvement
Current Medical Imaging