Chagas disease, also known as American trypanosomiasis, is a neglected tropical disease that poses a serious threat to public health in South and Central America, but not only there. The disease affects large groups of people in underdeveloped areas, causing around 12,000 deaths every year. There is no effective treatment for the chronic phase of the disease, while the drug-resistant strains of the Trypanosoma cruzi parasite start challenging the usefulness of the acute phase treatment. Consequently, new drug candidates need to be developed. This paper proposes a novel drug candidate that was created by optimising the lead molecule called CBZ-GlcN. The affinity of the reported drug candidate is exceptional (Kdiss = 7.11 nM), showing a 890-fold improvement over the affinity of CBZ-GlcN for TcGlcK. Furthermore, the new molecule exhibits advantageous pharmacokinetic properties. The paper also reports a suggested synthesis route for the drug candidate, which can be used to perform in vivo tests examining properties such as affinity, specificity, and toxicity of the drug candidate.
Inhaltsverzeichnis (Table of Contents)
- Abstract
- Introduction
- Methods
- Affinity
- Selectivity
- Pharmacokinetics
- Results
- Discussion
- Conclusion
Zielsetzung und Themenschwerpunkte (Objectives and Key Themes)
The paper aims to develop a novel drug candidate for the treatment of Chagas disease by optimizing the lead molecule CBZ-GlcN. The drug candidate is designed to target the enzyme T. cruzi glucokinase (TcGlcK), which is essential for the parasite's survival.
- Development of a novel drug candidate for Chagas disease
- Optimization of the lead molecule CBZ-GlcN
- Targeting the enzyme TcGlcK
- Improving affinity and pharmacokinetic properties
- Investigating selectivity against human glucokinase
Zusammenfassung der Kapitel (Chapter Summaries)
- Abstract: Introduces Chagas disease, its impact on public health, and the need for new drug candidates. Outlines the development of a novel drug candidate through optimization of the lead molecule CBZ-GlcN and highlights its improved affinity and pharmacokinetic properties.
- Introduction: Provides a detailed background on Chagas disease, its causes, and the limitations of current treatment options. It emphasizes the urgent need for new medications to address the challenges posed by the chronic phase of the disease and drug-resistant strains of the parasite.
- Methods: Describes the computational methods used for affinity calculations, selectivity assessment, and pharmacokinetic property prediction. It outlines the software used, the specific procedures employed, and the rationale behind the approach.
- Results: Presents the findings related to the affinity of the optimized molecule, its selectivity against human glucokinase, and its pharmacokinetic properties. The results are presented in a clear and concise manner, highlighting the significant improvements achieved.
- Discussion: Analyzes the results obtained and discusses their implications for the development of a successful drug candidate for Chagas disease. It explores the mechanisms of action, potential challenges, and future directions for research.
Schlüsselwörter (Keywords)
Chagas disease, American trypanosomiasis, Trypanosoma cruzi, drug discovery, lead optimization, TcGlcK, glucokinase, inhibitor, affinity, selectivity, pharmacokinetics, CBZ-GlcN, drug resistance.
- Quote paper
- Maciej Nodzyński (Author), 2023, Chagas disease. Discovery of a TcGlcK inhibitor through lead optimisation of CBZ-GlcN, Munich, GRIN Verlag, https://www.grin.com/document/1381846
