Abstract
The cell division cycle 25 (Cdc25) family of proteins is a group of highly conserved dual specificity phosphatases that regulate cyclin-dependent kinases and represent a group of attractive drug targets for anticancer therapies. To develop novel Cdc25B inhibitors, the ZINC database was screened for finding optimal fragments with de novo design approaches. As a result, top 11 compounds with higher binding affinities in flexible docking were obtained, which were derived from five novel scaffolds (scaffold C) consisting of the linker-part and two isolated scaffolds (scaffold A and B)located in the two binding domains (catalytic pocket and swimming pool), respectively. The subsequent molecular docking and molecular dynamics studies showed that these compounds not only adopt more favorable conformations but also have stronger binding interaction with receptor than the inhibitors identified previously. The additional absorption, distribution, metabolism, excretion and toxicity (ADMET) predictions also indicted that the 11 compounds (especially Comp#1) hold a high potential to be novel lead compounds for anticarcinogen. Consequently, the findings reported here may at least provide a new strategy or useful insights for designing effective Cdc25B inhibitors.
Keywords: ADMET, cancer, Cdc25B inhibitors, de novo design, drug design, molecular dynamics.
Combinatorial Chemistry & High Throughput Screening
Title:Design Novel Inhibitors for Treating Cancer by Targeting Cdc25B Catalytic Domain with De Novo Design
Volume: 17 Issue: 10
Author(s): Jing-Wei Wu, Huan Zhang, Yu-Qing Duan, Wei-Li Dong, Xian-Chao Cheng, Shu-Qing Wang and Run-Ling Wang
Affiliation:
Keywords: ADMET, cancer, Cdc25B inhibitors, de novo design, drug design, molecular dynamics.
Abstract: The cell division cycle 25 (Cdc25) family of proteins is a group of highly conserved dual specificity phosphatases that regulate cyclin-dependent kinases and represent a group of attractive drug targets for anticancer therapies. To develop novel Cdc25B inhibitors, the ZINC database was screened for finding optimal fragments with de novo design approaches. As a result, top 11 compounds with higher binding affinities in flexible docking were obtained, which were derived from five novel scaffolds (scaffold C) consisting of the linker-part and two isolated scaffolds (scaffold A and B)located in the two binding domains (catalytic pocket and swimming pool), respectively. The subsequent molecular docking and molecular dynamics studies showed that these compounds not only adopt more favorable conformations but also have stronger binding interaction with receptor than the inhibitors identified previously. The additional absorption, distribution, metabolism, excretion and toxicity (ADMET) predictions also indicted that the 11 compounds (especially Comp#1) hold a high potential to be novel lead compounds for anticarcinogen. Consequently, the findings reported here may at least provide a new strategy or useful insights for designing effective Cdc25B inhibitors.
Export Options
About this article
Cite this article as:
Wu Jing-Wei, Zhang Huan, Duan Yu-Qing, Dong Wei-Li, Cheng Xian-Chao, Wang Shu-Qing and Wang Run-Ling, Design Novel Inhibitors for Treating Cancer by Targeting Cdc25B Catalytic Domain with De Novo Design, Combinatorial Chemistry & High Throughput Screening 2014; 17 (10) . https://dx.doi.org/10.2174/1386207317666141029223505
DOI https://dx.doi.org/10.2174/1386207317666141029223505 |
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
-
Exercise Addiction- Diagnosis, Bio-Psychological Mechanisms and Treatment Issues
Current Pharmaceutical Design Identification of Bioactive Natural Products by Pharmacophore-Based Virtual Screening
Current Pharmaceutical Design Pharmacological and Non-pharmacological Therapies of Cognitive Impairment in Multiple Sclerosis
Current Neuropharmacology Recent Patents on Positive Allosteric Modulators of the Metabotropic Glutamate 5 Receptor as a Potential Treatment for Schizophrenia
Recent Patents on CNS Drug Discovery (Discontinued) Newer Avenues for the Treatment of Leptomeningeal Carcinomatosis
Central Nervous System Agents in Medicinal Chemistry Efficacy and Cardiovascular Safety of Antidiabetic Medications
Current Drug Safety Attention Deficit Hyperactive Disorder and Occurrence of Tic Disorders in Children and Adolescents—What is the Verdict
Current Pediatric Reviews Utilising Nanotechnology and Nanosystems for Treatment of Rare Diseases
Pharmaceutical Nanotechnology Immunomodulatory Roles of VIP and PACAP in Models of Multiple Sclerosis
Current Pharmaceutical Design Relationships Between the Structural Properties of Flavonoids and their Inhibitory Activities Against Matrix Metallopeptidase 9
Letters in Drug Design & Discovery RNA Therapeutics Directed to the Non Coding Regions of APP mRNA, In Vivo Anti-Amyloid Efficacy of Paroxetine, Erythromycin, and N-acetyl cysteine
Current Alzheimer Research Patent Selections:
Recent Patents on Drug Delivery & Formulation Hypothalamic and Neuroendocrine Changes in Huntingtons Disease
Current Drug Targets Current and Future Perspectives on the Major Depressive Disorder: Focus on the New Multimodal Antidepressant Vortioxetine
CNS & Neurological Disorders - Drug Targets The Metaboloepigenetic Dimension of Cancer Stem Cells: Evaluating the Market Potential for New Metabostemness-Targeting Oncology Drugs
Current Pharmaceutical Design Alkaloids from Piper: A Review of its Phytochemistry and Pharmacology
Mini-Reviews in Medicinal Chemistry Nicotinamide: Oversight of Metabolic Dysfunction Through SIRT1, mTOR, and Clock Genes
Current Neurovascular Research Meet Our Editorial Board Member:
Endocrine, Metabolic & Immune Disorders - Drug Targets Malignant Hyperthermia: A Pharmacogenetic Disease of Ca++ Regulating Proteins
Current Molecular Medicine Vagotomy and Gastric Tumorigenesis
Current Neuropharmacology