Abstract
Farnesyltransferase (FTase) and geranylgeranyltransferase type-I (GGTase-I) are two members of protein prenyltransferases, which play critical roles in lipid post-translational modifications. Potent inhibitors of FTase and GGTase-I have been confirmed to show favorable influence on the therapies of various diseases, such as cancers, malaria and Toxoplasmosis. However, designing highly specific inhibitors toward FTase or GGTase-I without influencing their binding affinity remains a big challenge. In this work, molecular docking, molecular dynamics (MD) simulations and MM/GBSA free energy calculations were employed to study the bindings of two highly selective inhibitors (lonafarnib and GGTI-2133) towards FTase or GGTase-I. The specificities of the studied inhibitors derived from the predicted binding free energies are consistent with the experimental data. The analysis of the energetic components illustrates that both the non-polar and polar interactions play critical roles in determining the specificity between FTase and GGTase-I. Moreover, the protein-inhibitor interaction spectra for the studied inhibitors were determined through the decomposition of the binding free energies, and the important residues for binding and specificity were highlighted. Our study provides useful information for the rational design of selective FTase or GGTase-I inhibitors.
Keywords: Free energy decomposition, FTase, GGTase-I, MM/GBSA, molecular docking, molecular dynamics simulations, Prenyltransferase, specificity.
Combinatorial Chemistry & High Throughput Screening
Title:Theoretical Studies on Binding and Specificity Mechanisms of Farnesyltransferase (FTase) and Geranylgeranyltransferase Type-I (GGTase-I) Inhibitors by Molecular Modeling
Volume: 17 Issue: 6
Author(s): Shirou Zhou
Affiliation:
Keywords: Free energy decomposition, FTase, GGTase-I, MM/GBSA, molecular docking, molecular dynamics simulations, Prenyltransferase, specificity.
Abstract: Farnesyltransferase (FTase) and geranylgeranyltransferase type-I (GGTase-I) are two members of protein prenyltransferases, which play critical roles in lipid post-translational modifications. Potent inhibitors of FTase and GGTase-I have been confirmed to show favorable influence on the therapies of various diseases, such as cancers, malaria and Toxoplasmosis. However, designing highly specific inhibitors toward FTase or GGTase-I without influencing their binding affinity remains a big challenge. In this work, molecular docking, molecular dynamics (MD) simulations and MM/GBSA free energy calculations were employed to study the bindings of two highly selective inhibitors (lonafarnib and GGTI-2133) towards FTase or GGTase-I. The specificities of the studied inhibitors derived from the predicted binding free energies are consistent with the experimental data. The analysis of the energetic components illustrates that both the non-polar and polar interactions play critical roles in determining the specificity between FTase and GGTase-I. Moreover, the protein-inhibitor interaction spectra for the studied inhibitors were determined through the decomposition of the binding free energies, and the important residues for binding and specificity were highlighted. Our study provides useful information for the rational design of selective FTase or GGTase-I inhibitors.
Export Options
About this article
Cite this article as:
Zhou Shirou, Theoretical Studies on Binding and Specificity Mechanisms of Farnesyltransferase (FTase) and Geranylgeranyltransferase Type-I (GGTase-I) Inhibitors by Molecular Modeling, Combinatorial Chemistry & High Throughput Screening 2014; 17 (6) . https://dx.doi.org/10.2174/1386207317666140120122920
DOI https://dx.doi.org/10.2174/1386207317666140120122920 |
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
-
Restoration of Antitumor Immunity Through Selective Inhibition of Myeloid Derived Suppressor Cells by Anticancer Therapies
Current Molecular Medicine Gene Expression Significance in Personalized Medicine of Non-small Cell Lung Cancer and Gene Expression Analyzing Platforms
Current Drug Metabolism HPV and Therapeutic Vaccines: Where are We in 2010?
Current Cancer Therapy Reviews Fiber-Optic Technologies in Laser-Based Therapeutics: Threads for a Cure
Current Pharmaceutical Biotechnology Taxol: Efficacy Against Oral Squamous Cell Carcinoma
Mini-Reviews in Medicinal Chemistry Hypericin - A New Antiviral and Antitumor Photosensitizer: Mechanism of Action and Interaction with Biological Macromolecules
Current Drug Targets The Thyroid Gland: A Crossroad in Inflammation-Induced Carcinoma? An Ongoing Debate with New Therapeutic Potential.
Current Medicinal Chemistry Death Receptor Ligands: New Strategies for Combined Treatment with Ionizing Radiation
Current Medicinal Chemistry - Anti-Cancer Agents Hybrid PET/MRI for In Vivo Imaging of Cancer: Current Clinical Experiences and Recent Advances
Current Medical Imaging The Akt Pathway: Molecular Targets for Anti-Cancer Drug Development
Current Cancer Drug Targets Across the Universe of K-Ras Mutations in Non-Small-Cell-Lung Cancer
Current Pharmaceutical Design Targeting the Eph-ephrin System with Protein-Protein Interaction (PPI) Inhibitors
Current Drug Targets Inhibitors of the Hedgehog Signal Transduction Pathway
Current Cancer Therapy Reviews Berberine: A Fluorescent Alkaloid with a Variety of Applications from Medicine to Chemistry
Mini-Reviews in Organic Chemistry Angiogenesis and Metastasis Inhibitors for the Treatment of Malignant Melanoma
Mini-Reviews in Medicinal Chemistry The Exploitation of Toll-like Receptor 3 Signaling in Cancer Therapy
Current Pharmaceutical Design Cell-free DNA: Characteristics, Detection and its Applications in Myocardial Infarction
Current Pharmaceutical Design Molecular Targeting Agents in Renal Cell Carcinoma: Present Strategies and Future Perspectives
Current Pharmaceutical Design Genetic and Epigenetic Regulation of Phosphoinositide 3-kinase Isoforms
Current Pharmaceutical Design Editorial [ Hot Topic: Targeting Tumor Angiogenesis: An Update (Guest Editor: Girolamo Ranieri)]
Current Medicinal Chemistry