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.
Table of Contents
1. Introduction
2. Methods
2.1 Affinity
2.2 Selectivity
2.3 Pharmacokinetics
2.4 Synthesis
3. Results
3.1 Affinity
3.2 Selectivity
3.3 Pharmacokinetics
3.4 Synthesis
4. Discussion
Research Objectives and Themes
The primary goal of this research is to identify and develop a novel, potent, and selective drug candidate for the chronic phase of Chagas disease by optimizing the lead molecule CBZ-GlcN. The study focuses on enhancing binding affinity to the target protein TcGlcK while ensuring high selectivity against human glucokinase and favorable pharmacokinetic properties.
- In-silico optimization of CBZ-GlcN through structure-based drug design.
- Evaluation of binding affinity and selectivity using docking simulations with YASARA and Autodock Vina.
- Computational analysis of pharmacokinetic profiles of lead and optimized compounds.
- Proposing a synthetic route for the novel optimized drug candidate.
Excerpt from the Book
Introduction
Chagas disease, also known as American trypanosomiasis, is a parasitic disease that can be contracted mainly in South and Central America, which are the endemic regions. Although this disease was discovered over 100 years ago, only in 2005 did it get the attention of the public when WHO recognised Chagas disease as a neglected tropical disease (who.int, 2023). Since then, knowledge about Chagas disease has expanded and the treatment has improved, but still, it causes around 12 thousand deaths per year, with approximately 7 million individuals being infected at the moment (who.int, 2023). The disease concerns especially people in tropical and underdeveloped areas where access to medical care is limited, which makes the whole issue even more serious (who.int, 2023). Chagas disease is caused by a parasite called Trypanosoma cruzi, which uses triatomine bugs (also known as kissing bugs) as vectors (who.int, 2023). Triatomine bugs are nocturnal animals that feed on animals' blood, including humans, and that is how the disease can spread (who.int, 2023). It is enough if an insect bites the skin and leaves some feces (where the parasite is found) near the wound. Then, an individual may scratch their skin during sleep and transfer the feces with the parasite into the wound and bloodstream. Infected individuals can experience chronic health problems, such as heart disease and digestive tract problems, which can emerge even decades after the initial infection (paho.org, 2023). Chagas disease can result in death if left untreated (who.int, 2023).
Summary of Chapters
1. Introduction: This chapter contextualizes Chagas disease as a neglected tropical health crisis and identifies T. cruzi glucokinase (TcGlcK) as a key drug target for therapeutic intervention.
2. Methods: This section details the computational procedures and software tools, including YASARA and Autodock Vina, used to perform the in-silico drug optimization and pharmacokinetic analysis.
3. Results: This chapter presents the optimized molecular structure, quantifying the significant improvements in binding affinity and ADME properties achieved through iterative modifications.
4. Discussion: This section evaluates the potential of the optimized candidate 4UZO, acknowledging the necessity for future in-vivo validation and discussing its prospective impact on treating Trypanosomiasis.
Keywords
Chagas disease, American trypanosomiasis, TcGlcK, CBZ-GlcN, Drug discovery, In-silico research, Molecular docking, Binding affinity, Pharmacokinetics, 4UZO, Selectivity, Trypanosoma cruzi, Medicinal chemistry, Lead optimization, Drug design.
Frequently Asked Questions
What is the core focus of this research paper?
This paper focuses on the lead optimization of the molecule CBZ-GlcN to discover a more effective and selective inhibitor of the T. cruzi glucokinase enzyme for the treatment of Chagas disease.
Which scientific methodology is employed?
The study utilizes in-silico medicinal chemistry techniques, specifically molecular docking simulations via YASARA and Autodock Vina, combined with computational pharmacokinetic assessments.
What is the main objective of the study?
The objective is to achieve a significant improvement in the binding affinity of the drug candidate compared to the original lead molecule while maintaining positive pharmacokinetic properties and high species selectivity.
Which specific protein is targeted to treat the disease?
The targeted protein is T. cruzi glucokinase (TcGlcK), which is essential for the parasite's glucose synthesis, growth, and differentiation.
How is the optimized drug candidate named?
The optimized candidate is referred to as 4UZO, derived from the ligand residue name 4UZ and the designation of 'Optimised'.
Why are pharmacokinetic properties evaluated?
Pharmacokinetic properties are evaluated to ensure that the drug candidate possesses good bioavailability, appropriate GI absorption, and adheres to Lipinski's Rule of Five for oral administration.
How much improvement in affinity was demonstrated by 4UZO?
The optimized candidate 4UZO demonstrated an exceptional affinity (Kdiss = 7.11 nM), representing an 890-fold improvement compared to the lead molecule CBZ-GlcN.
What is the result regarding species selectivity?
The docking analysis performed on human glucokinase (HGlcK) confirmed that 4UZO is selective for the parasite-specific enzyme, showing significantly weaker affinity for the human protein compared to TcGlcK.
What does the synthesis section propose?
The synthesis section provides a proposed multi-step laboratory route for creating 4UZO, confirming the chemical accessibility of the proposed drug candidate.
- 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
