Abstract
In this paper, we discussed our recent experience with the use of computational modeling tools in studying the binding interaction of small molecular weight ligands with their protein targets. Specific examples discussed here include the interaction of estrogens with human protein disulfide isomerase (PDI) and its pancreas-specific homolog (PDIp), and the interaction of dietary flavonoids with human cyclooxygenase (COX) I and II. Using human PDIp as an example, biochemical analysis revealed that the estrogen-binding activity is only associated with PDIp’s b-b´ domain combination but not associated with the single b or b´ domain or any other domains. Homology modeling was then used to build a threedimensional structure of the human PDIp’s b-b´ fragment. Docking analyses predicted that a hydrogen bond, formed between the 3-hydroxyl group of estradiol and His278 of PDIp’s E2-binding site, is critical for the binding interaction. This binding model was then experimentally confirmed by a series of experiments, such as selective mutations of the predicted binding site amino acid residues and the selective modifications of the functional groups of the ligands. Similar combinatorial approaches were used successfully to identify the binding site structure of human PDI for estradiol and the binding site structures of human COX I and II for their phenolic co-substrates. The success with these combinatorial approaches provides the basis for using computational modeling-guided approaches in characterizing the ligand binding site structures of complex proteins whose structures are difficult to decipher with crystallographic studies.
Current Medicinal Chemistry
Title:Usefulness of Molecular Modeling in Characterizing the Ligand-Binding Sites of Proteins: Experience with Human PDI, PDIp and COX
Volume: 20 Issue: 31
Author(s): Pan Wang and Bao-Ting Zhu
Affiliation:
Abstract: In this paper, we discussed our recent experience with the use of computational modeling tools in studying the binding interaction of small molecular weight ligands with their protein targets. Specific examples discussed here include the interaction of estrogens with human protein disulfide isomerase (PDI) and its pancreas-specific homolog (PDIp), and the interaction of dietary flavonoids with human cyclooxygenase (COX) I and II. Using human PDIp as an example, biochemical analysis revealed that the estrogen-binding activity is only associated with PDIp’s b-b´ domain combination but not associated with the single b or b´ domain or any other domains. Homology modeling was then used to build a threedimensional structure of the human PDIp’s b-b´ fragment. Docking analyses predicted that a hydrogen bond, formed between the 3-hydroxyl group of estradiol and His278 of PDIp’s E2-binding site, is critical for the binding interaction. This binding model was then experimentally confirmed by a series of experiments, such as selective mutations of the predicted binding site amino acid residues and the selective modifications of the functional groups of the ligands. Similar combinatorial approaches were used successfully to identify the binding site structure of human PDI for estradiol and the binding site structures of human COX I and II for their phenolic co-substrates. The success with these combinatorial approaches provides the basis for using computational modeling-guided approaches in characterizing the ligand binding site structures of complex proteins whose structures are difficult to decipher with crystallographic studies.
Export Options
About this article
Cite this article as:
Wang Pan and Zhu Bao-Ting, Usefulness of Molecular Modeling in Characterizing the Ligand-Binding Sites of Proteins: Experience with Human PDI, PDIp and COX, Current Medicinal Chemistry 2013; 20 (31) . https://dx.doi.org/10.2174/09298673113209990207
DOI https://dx.doi.org/10.2174/09298673113209990207 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread 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
-
Combination of Photodynamic Therapy with Anti-Cancer Agents
Current Medicinal Chemistry Matrix Metalloproteinase Inhibitors as Prospective Agents for the Prevention and Treatment of Cardiovascular and Neoplastic Diseases
Current Topics in Medicinal Chemistry Power from the Garden: Plant Compounds as Inhibitors of the Hallmarks of Cancer
Current Medicinal Chemistry New Approaches in Glioblastoma Multiforme: The Potential Role of Immune- check Point Inhibitors
Current Cancer Drug Targets Cholangiocarcinoma Therapeutics: An Update
Current Cancer Drug Targets Animal Peptides Targeting Voltage-Activated Sodium Channels
Current Pharmaceutical Design Targeting IL-17 and IL-23 in Immune Mediated Renal Disease
Current Medicinal Chemistry An Overview of Piperazine Scaffold as Promising Nucleus for Different Therapeutic Targets
Current Pharmaceutical Design Efficacy of Therapy with c-Met/HGF Inhibitors in Solid Tumors: A Systematic Review Based on 24 Clinical Trials
Clinical Cancer Drugs Prospects of Nanocarriers for Oral Delivery of Bioactives Using Targeting Strategies
Current Pharmaceutical Biotechnology DNA Repair Proteins as Molecular Targets for Cancer Therapeutics
Anti-Cancer Agents in Medicinal Chemistry Depression has a Strong Relationship to Alterations in the Immune, Endocrine and Neural System
Current Psychiatry Reviews Adiponectin: Merely a Bystander or the Missing Link to Cardiovascular Disease?
Current Topics in Medicinal Chemistry Immunotherapy of Human Cancers Using Gene Modified T Lymphocytes
Current Gene Therapy Purification and Characterization of a Lectin from the Indian Cultivar of French Bean Seeds
Protein & Peptide Letters Computational Medicinal Chemistry to Design Novel Phosphoinositide 3- Kinase (PI3K) Alpha Inhibitors in View of Cancer
Current Bioactive Compounds Traditional Uses, Phytochemistry, Pharmacology and Anticancer Activity of Açaí (Euterpe oleracea Mart): A Narrative Review
Current Traditional Medicine Radiation Induced Non-targeted Response: Mechanism and Potential Clinical Implications
Current Molecular Pharmacology Macrophage-Assisted Inflammation and Pharmacological Regulation of the Cholinergic Anti-Inflammatory Pathway
Current Medicinal Chemistry Is There a Role for Antioxidants in the Prevention of Infection-Associated Carcinogenesis and in the Treatment of Infection-Driven Tumors?
Current Topics in Medicinal Chemistry