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
- 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
-
Edelfosine in Membrane Environment - the Langmuir Monolayer Studies
Anti-Cancer Agents in Medicinal Chemistry Herpes Simplex Virus Type 1 Amplicons and their Hybrid Virus Partners, EBV, AAV, and Retrovirus
Current Gene Therapy The Epigenetics of Breast Carcinogenesis and Metastasis
Current Genomics Active Metabolites Resulting from Decarboxylation, Reduction and Ester Hydrolysis of Parent Drugs
Current Drug Metabolism Effects of Amine Oxidases in Allergic and Histamine-Mediated Conditions
Recent Patents on Inflammation & Allergy Drug Discovery Microarrays as a Tool for Gene Expression Profiling: Application in Ocular and Craniofacial Research
Current Pharmaceutical Analysis SUBJECT INDEX TO VOLUME 1
Current Pharmaceutical Biotechnology Folate Receptor Targeted Liposomes Encapsulating Anti-Cancer Drugs
Current Pharmaceutical Biotechnology Cancer Prevention and Therapy in a Preclinical Mouse Model: Impact of FHIT Viruses
Current Gene Therapy Hematopoietic Stem Cell Transplantation for Thalassemia
Current Stem Cell Research & Therapy Plant-Made Antibodies: Properties and Therapeutic Applications
Current Medicinal Chemistry Disseminated Intravascular Coagulation in Leukemia and Sepsis
Vascular Disease Prevention (Discontinued) Rexinoids for Prevention and Treatment of Cancer: Opportunities and Challenges
Current Topics in Medicinal Chemistry Immune Therapy in Pancreatic Cancer: Now and the Future?
Reviews on Recent Clinical Trials Role of mTOR in Hematological Malignancies
Current Cancer Therapy Reviews Progress in Multiple Sclerosis Genetics
Current Genomics Therapeutic and Diagnostic Applications of Nanoparticles
Current Drug Targets Study of Serum Soluble Programmed Death Ligand 1 as a Prognostic Factor in Hepatocellular Carcinoma in Egyptian Patients
Current Cancer Drug Targets Third Generation Radiopharmaceuticals for Imaging and Targeted Therapy
Current Pharmaceutical Analysis Bio-Distribution, Imaging Protocols and Diagnostic Accuracy of PET with Tracers of Lipogenesis in Imaging Prostate Cancer: a Comparison between 11C-Choline, 18FFluoroethylcholine and 18F-Methylcholine
Current Pharmaceutical Design