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Updated: Aug 2, 2025
Identification of Novel CK2 Kinase Substrates Using a Versatile Biochemical Approach
Published on: February 21, 2019
Identification of Novel Tau-Tubulin Kinase 2 Inhibitors Using Computational Approaches
Shahzaib Ahamad1, Kanipakam Hema1, Dinesh Gupta1
1Translational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg, New Delhi 110067, India.
Abstract:
Tau tubulin kinase 2 (TTBK2) associated with multiple diseases is one of the kinases which phosphorylates tau and tubulin. Numerous efforts have been made to understand the role of TTBK2 in protein folding mechanisms and misfolding behavior. The misfolded protein intermediates form polymers with unwanted aggregation properties that initiate several diseases, including Alzheimer's. The availability of TTBK2 inhibitors can enhance the understanding of the molecular mechanism of action of the kinase and assist in developing novel therapeutics. In the quest for TTBK2 inhibitors, this study focuses on screening two chemical libraries (ChEMBL and ZINC-FDA). The molecular docking, RO5/absorption, distribution, metabolism, and excretion/toxicity, density functional theory, molecular dynamics (MD) simulations, and molecular mechanics with generalized Born and surface area solvation techniques enabled shortlisting of the four most active compounds, namely, ChEMBL1236395, ChEMBL2104398, ChEMBL3427435, and ZINC000000509440. Moreover, 500 ns MD simulation was performed for each complex, which provided valuable insights into the structural changes in the complexes. The relative fluctuation, solvent accessible surface area, atomic gyration, compactness covariance, and free energy landscapes revealed that the compounds could stabilize the TTBK2 protein. Overall, this study would be valuable for the researchers targeting the development of novel TTBK2 inhibitors.
Insights
Researchers screened chemical libraries to identify Tau Tubulin Kinase 2 (TTBK2) inhibitors. Four compounds showed potential to stabilize TTBK2, aiding in the development of new therapeutics for diseases linked to protein misfolding.
Area of Science:
- Biochemistry and Molecular Biology
- Neuroscience
- Drug Discovery
Background:
- Tau Tubulin Kinase 2 (TTBK2) is implicated in diseases driven by protein misfolding, such as Alzheimer's.
- Understanding TTBK2's role in protein folding and misfolding is crucial for therapeutic development.
- Developing specific TTBK2 inhibitors can elucidate its mechanism of action and aid in novel drug design.
Purpose of the Study:
- To identify potential inhibitors of Tau Tubulin Kinase 2 (TTBK2) through chemical library screening.
- To evaluate the efficacy and binding stability of identified compounds with TTBK2.
- To provide insights for the development of novel therapeutics targeting TTBK2-related diseases.
Main Methods:
- Screening of ChEMBL and ZINC-FDA chemical libraries.
- Utilizing molecular docking, RO5 (drug-likeness properties), density functional theory, and molecular dynamics (MD) simulations.
- Employing molecular mechanics with generalized Born and surface area solvation (MM/GBSA) for binding free energy calculations.
Main Results:
- Four lead compounds (ChEMBL1236395, ChEMBL2104398, ChEMBL3427435, ZINC000000509440) were shortlisted.
- 500 ns MD simulations demonstrated that these compounds could stabilize the TTBK2 protein structure.
- Analysis of various parameters (fluctuation, solvent accessible surface area, gyration, etc.) confirmed compound-protein stability.
Conclusions:
- The identified compounds show promise as TTBK2 inhibitors.
- These findings offer a valuable foundation for researchers developing novel TTBK2-targeted therapeutics.
- The study contributes to understanding TTBK2's role in disease pathogenesis and inhibitor design.
