Abstract
Affinity selection of peptides displayed on phage particles was used as the basis for mapping molecular contacts between small molecule ligands and their protein targets. Analysis of the crystal structures of complexes between proteins and small molecule ligands revealed that virtually all ligands of molecular weight 300 Da or greater have a continuous binding epitope of 5 residues or more. This observation led to the development of a technique for binding site identification which involves statistical analysis of an affinity-selected set of peptides obtained by screening of libraries of random, phage-displayed peptides against small molecules attached to solid surfaces. A random sample of the selected peptides is sequenced and used as input for a similarity scanning program which calculates cumulative similarity scores along the length of the putative receptor. Regions of the protein sequence exhibiting the highest similarity with the selected peptides proved to have a high probability of being involved in ligand binding. This technique has been employed successfully to map the contact residues in multiple known targets of the anticancer drugs paclitaxel (Taxol™), docetaxel (Taxotere™) and 2-methoxyestradiol and the glycosaminoglycan hyaluronan, and to identify a novel paclitaxel receptor [1]. These data corroborate the observation that the binding properties of peptides displayed on the surface of phage particles can mimic the binding properties of peptides in naturally occurring proteins. It follows directly that structural context is relatively unimportant for determining the binding properties of these disordered peptides. This technique represents a novel, rapid, high resolution method for identifying potential ligand binding sites in the absence of three-dimensional information and has the potential to greatly enhance the speed of development of novel small molecule pharmaceuticals.
Combinatorial Chemistry & High Throughput Screening
Title: Identification of Small Molecule Binding Sites within Proteins Using Phage Display Technology
Volume: 4 Issue: 7
Author(s): D. J. Rodi, G. E. Agoston, R. Manon, R. Lapcevich, S. J. Green and L. Makowski
Affiliation:
Abstract: Affinity selection of peptides displayed on phage particles was used as the basis for mapping molecular contacts between small molecule ligands and their protein targets. Analysis of the crystal structures of complexes between proteins and small molecule ligands revealed that virtually all ligands of molecular weight 300 Da or greater have a continuous binding epitope of 5 residues or more. This observation led to the development of a technique for binding site identification which involves statistical analysis of an affinity-selected set of peptides obtained by screening of libraries of random, phage-displayed peptides against small molecules attached to solid surfaces. A random sample of the selected peptides is sequenced and used as input for a similarity scanning program which calculates cumulative similarity scores along the length of the putative receptor. Regions of the protein sequence exhibiting the highest similarity with the selected peptides proved to have a high probability of being involved in ligand binding. This technique has been employed successfully to map the contact residues in multiple known targets of the anticancer drugs paclitaxel (Taxol™), docetaxel (Taxotere™) and 2-methoxyestradiol and the glycosaminoglycan hyaluronan, and to identify a novel paclitaxel receptor [1]. These data corroborate the observation that the binding properties of peptides displayed on the surface of phage particles can mimic the binding properties of peptides in naturally occurring proteins. It follows directly that structural context is relatively unimportant for determining the binding properties of these disordered peptides. This technique represents a novel, rapid, high resolution method for identifying potential ligand binding sites in the absence of three-dimensional information and has the potential to greatly enhance the speed of development of novel small molecule pharmaceuticals.
Export Options
About this article
Cite this article as:
Rodi J. D., Agoston E. G., Manon R., Lapcevich R., Green J. S. and Makowski L., Identification of Small Molecule Binding Sites within Proteins Using Phage Display Technology, Combinatorial Chemistry & High Throughput Screening 2001; 4 (7) . https://dx.doi.org/10.2174/1386207013330779
DOI https://dx.doi.org/10.2174/1386207013330779 |
Print ISSN 1386-2073 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5402 |
Call for Papers in Thematic Issues
Artificial Intelligence Methods for Biomedical, Biochemical and Bioinformatics Problems
Recently, a large number of technologies based on artificial intelligence have been developed and applied to solve a diverse range of problems in the areas of biomedical, biochemical and bioinformatics problems. By utilizing powerful computing resources and massive amounts of data, methods based on artificial intelligence can significantly improve the ...read more
Eco-friendly Agents for Biological Control of Pathogenic Diseases
The discovery of an alternative biological approach to disease management includes work on medicinal products derived from natural sources as a starting point for the development of eco-friendly agents for these diseases and the injuries they cause, as well as reducing human contact with hazardous chemicals and their residues. We ...read more
Emerging trends in diseases mechanisms, noble drug targets and therapeutic strategies: focus on immunological and inflammatory disorders
Recently infectious and inflammatory diseases have been a key concern worldwide due to tremendous morbidity and mortality world Wide. Recent, nCOVID-9 pandemic is a good example for the emerging infectious disease outbreak. The world is facing many emerging and re-emerging diseases out breaks at present however, there is huge lack ...read more
Exploring Spectral Graph Theory in Combinatorial Chemistry
Scope of the Thematic Issue: Combinatorial chemistry involves the synthesis and analysis of a large number of diverse compounds simultaneously. Traditional methods rely on brute force experimentation, which can be time-consuming and resource-intensive. Spectral Graph Theory, a branch of mathematics dealing with the properties of graphs in relation to the ...read more
![](/images/wayfinder.jpg)
- 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
Related Articles
-
Glioblastoma Multiforme Imaging: The Role of Nuclear Medicine
Current Radiopharmaceuticals Disulfiram's Anticancer Activity: Evidence and Mechanisms
Anti-Cancer Agents in Medicinal Chemistry Therapeutic Potential of Lymphoid Infiltrates in Breast Cancer
Current Medicinal Chemistry Flexible Bronchoscopy Biopsy Tools and Techniques to Optimize Diagnostic Yield: A Contemporary Review
Current Respiratory Medicine Reviews Imidazo[4,5-<i>b</i>]Pyridines: From Kinase Inhibitors to more Diversified Biological Properties
Current Medicinal Chemistry Hepatocarcinogenesis and Ceramide/Cholesterol Metabolism
Anti-Cancer Agents in Medicinal Chemistry Histone Deacetylase Inhibitors in the Treatment of Hematological Malignancies
Mini-Reviews in Medicinal Chemistry Preclinical Metabolism and Pharmacokinetics of SB1317 (TG02), a Potent CDK/JAK2/FLT3 Inhibitor
Drug Metabolism Letters Recent Advances in Radiopharmaceutical Application of Matched-Pair Radiometals
Current Topics in Medicinal Chemistry Achievements in Cancer Research and its Therapeutics in Hundred Years
Current Topics in Medicinal Chemistry Reduction in Ischemic Cerebral Infarction is Mediated through Golgi Phosphoprotein 3 and Akt/mTOR Signaling Following Salvianolate Administration
Current Neurovascular Research The Role of H. pylori Infection in Diabetes
Current Diabetes Reviews Cell Death Targeting Therapies in B Lymphoid Malignancies
Current Drug Targets Carbohydrate based Potential Chemotherapeutic Agents: Recent Developments and their Scope in Future Drug Discovery
Mini-Reviews in Medicinal Chemistry Withdrawal Notice: Recent Developments in Anti-Cancer Activity of Compounds Containing the Thioether Group
Anti-Cancer Agents in Medicinal Chemistry Potential of Plant-Derived Natural Products in the Treatment of Leukemia and Lymphoma
Current Drug Targets Experimental Onco-Immunology Revisited
Current Cancer Therapy Reviews Synthesis of Drugs and Biorelevant N-heterocycles Employing Recent Advances in C-N Bond Formation
Current Organic Chemistry Antimicrobial Sulfated Glycans: Structure and Function
Current Topics in Medicinal Chemistry The Role of Peptidyl Prolyl Isomerases in Aging and Vascular Diseases
Current Molecular Pharmacology