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Halogens engineering-based design of agonists for boosting expression of frataxin protein in Friedreich's ataxia
1Department of Biotechnology, Faculty of Science & Technology, University of Central Punjab, Lahore, Pakistan. Dr.naveed@ucp.edu.pk.
Insights
This study developed a novel halogen-optimized agonist to increase frataxin protein expression, offering a potential new treatment for Friedreich
Area of Science:
- Neuroscience and Pharmacology
- Molecular Biology
- Computational Chemistry
Background:
- Friedreich's ataxia (FA) is a neurodegenerative disorder caused by decreased mitochondrial frataxin expression.
- High mortality rates, up to 66%, are observed in FA patients with cardiac complications.
- Developing effective treatments for FA is crucial due to its severe impact.
Purpose of the Study:
- To investigate novel halogenated compounds for effective Friedreich's ataxia treatment.
- To identify potent agonist compounds for targeting the Frataxin Protein.
- To evaluate drug-like properties and efficacy of optimized compounds.
Main Methods:
- Screening of twenty agonist compounds using molecular docking against the Frataxin Protein.
- Optimization of the most promising compound through halogenation.
- ADMET profiling, Lipinski's rule of five assessment, and molecular dynamic simulations.
Main Results:
- A potent agonist compound was identified with a binding energy of -10.4 Kcal/mol.
- The optimized agonist demonstrated favorable drug-like properties, including good GI absorption and fulfillment of Lipinski's rule.
- Molecular dynamic simulations indicated efficient behavior of the candidate compound.
Conclusions:
- The identified halogen-optimized agonist is a potent enhancer of Frataxin protein expression.
- Halogenation is a promising strategy for improving drug efficacy in Friedreich's ataxia treatment.
- Computational findings support the development of effective medications for Friedreich's ataxia.
Objective:
Decreased expression of the mitochondrial protein frataxin is the cause of the neurodegenerative disorder Friedreich's ataxia. In patients with cardiac disorders, the death rate of this disease is very high, up to 66%. In order to combat Friedreich ataxia, which is a potentially toxic disorder, de novo drug discovery and design have been created utilizing the approach of compound engineering with halogens. This study aimed to investigate the potential for effective treatment of Friedreich ataxia.
Materials And Methods:
The screening of twenty different agonist compounds was carried out in order to find the most promising agonist compound that may be used for molecular docking prediction against the Frataxin Protein. The compound with the lowest binding energies is then optimized by halogens. The final candidate's drug-like properties are identified through Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiling. Lipinski's rule of five was checked. Molecular dynamic stimulations were evaluated.
Results:
The most potent agonist compound was identified out of twenty different compounds utilizing a docking approach against the Frataxin Protein. The compound with the lowest binding energies was next subjected to optimization by halogens. The optimized agonist 9-[1-[(1S, 5R)-8, 8-dimethyl-8-azoniabicyclo[3.2.1]octan-3-yl]triazol-4-yl]fluoren-9-ol has higher binding energy of -10.4Kcal/mol with molecular weight of 705.63 g/mol. Drug-like properties are identified through ADMET profiling, having water solubility of about -7.59, skin permeation -7.08 cm/s, bioavailability score 0.17, and high GI absorption. The candidate fulfills the Lipinski rule of five and portrays efficient molecular dynamic stimulations.
Conclusions:
The selected agonist is one of the most potent compounds in increasing Frataxin protein expression. Furthermore, optimization with halogens can be a productive approach to improve the candidate's drug efficacy. The development of effective medications for the treatment of Friedreich ataxia would be aided by the results of these computational investigations.
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