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Author Spotlight: Purifying High-Quality Tubulin to Study Protein Dynamics and Therapeutic Applications
Published on: October 11, 2024
Exploring β-Tubulin Inhibitors from Plant Origin using Computational Approach
Kanika Verma1, Kaavya Kannan1, Shanthi V1
1Department of Biotechnology, School of Bio Sciences and Technology, VIT University, Vellore, 632014, Tamil Nadu, India.
Introduction:
β-Tubulin is an important target for the binding of anti-cancer drugs, in particular, paclitaxel (taxol), vinblastine and epothilone. However, mutations in β-tubulin structure give resistance to chemotherapeutic agents. Notably, mutations at R306C, F270 V, L217R, L228F, A185T and A248V positions in β-tubulin give high resistance for paclitaxel binding.
Objective:
To discover novel inhibitors of β-tubulin from natural sources, particularly alkaloids, using a virtual screening approach.
Methodology:
A virtual screening approach was employed to find potent lead molecules from the Naturally-occurring Plant-based Anti-cancer Compound-activity Target (NPACT) database. Alkaloids have great potential to be anti-cancer agents. Therefore, we have screened all alkaloids from a total of 1574 molecules from the NPACT database for our study. Initially, Molinspiration and DataWarrior programs were utilised to calculate pharmacokinetics and toxicity risks of the alkaloids, respectively. Subsequently, AutoDock algorithm was employed to understand the binding efficiency of alkaloids against β-tubulin. The binding affinity of the docked complex was confirmed by means of an intermolecular interaction study. Moreover, oral toxicity was predicted by using ProTox program. Further, metabolising capacity of drugs was studied by using SmartCYP software. Additionally, scaffold analysis was done with the help of scaffold trees and dendrograms, providing knowledge about the building blocks for parent-compound synthesis.
Results:
Overall, the results of our computational analysis indicate that isostrychnine, obtained from Strychnosnux-vomica, satisfies pharmacokinetic and bioavailability properties, binds efficiently with β-tubulin. Thus, it could be a promising lead for the treatment of paclitaxel resistant cancer types.
Conclusion:
This is the first observation of inhibitory activity of isostrychnine against β-tubulin and warrants further experimental investigation. Copyright © 2016 John Wiley & Sons, Ltd.
Insights
This study identifies isostrychnine as a potential new drug to combat paclitaxel-resistant cancers by inhibiting beta-tubulin. Further research is needed to confirm its effectiveness against cancer cells.
Area of Science:
- Computational chemistry
- Drug discovery
- Natural products
Background:
- Beta-tubulin is a key target for anti-cancer drugs like paclitaxel.
- Mutations in beta-tubulin can lead to resistance against chemotherapy.
- Specific mutations confer high resistance to paclitaxel binding.
Purpose of the Study:
- To identify novel beta-tubulin inhibitors from natural sources, specifically alkaloids.
- To utilize a virtual screening approach for discovering potential anti-cancer agents.
Main Methods:
- Virtual screening of the NPACT database for alkaloids.
- Pharmacokinetic and toxicity risk assessment using Molinspiration and DataWarrior.
- Binding efficiency analysis with beta-tubulin using AutoDock.
- Oral toxicity prediction and metabolic capacity assessment.
- Scaffold analysis for compound synthesis.
Main Results:
- Isostrychnine, from Strychnosnux-vomica, demonstrated favorable pharmacokinetic and bioavailability properties.
- Isostrychnine exhibited efficient binding with beta-tubulin.
- Isostrychnine shows promise for treating paclitaxel-resistant cancers.
Conclusions:
- This study is the first to report isostrychnine's inhibitory activity against beta-tubulin.
- Isostrychnine is a potential lead compound for developing new cancer therapies.
- Further experimental validation is recommended.
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