Unlocking the potential of approved drugs for the allosteric inhibition of tropomyosin-receptor kinase A using molecular docking and molecular dynamics studies

by Selleckchem | Dec 04 2023

Tropomyosin-receptor kinase A (TrkA) is the primary isoform among the tropomyosin-receptor kinases that have been associated with human cancer development, contributing to approximately 7.4% of all cancer cases. TrkA represents an attractive target for cancer treatment; however, currently available TrkA inhibitors face limitations in terms of resistance development and potential toxicity. Hence, the objective of this study was to identify new allosteric-approved inhibitors of TrkA that can overcome these challenges and be employed in cancer therapy. To achieve this goal, a screening of 9,923 drugs from the ChEMBL database was conducted to assess their repurposing potential using molecular docking. The top 49 drug candidates, exhibiting the highest docking scores (-11.569 to -7.962 kcal/mol), underwent MM-GBSA calculations to evaluate their binding energies. Delanzomib and tibalosin, the top two drugs with docking scores of -10.643 and -10.184 kcal/mol, respectively, along with MM-GBSA dG bind values of -67.96 and -50.54 kcal/mol, were subjected to 200 ns molecular dynamic simulations, confirming their stable interactions with TrkA. Based on these findings, we recommend further experimental evaluation of delanzomib and tibalosin to determine their potential as allosteric inhibitors of TrkA. These drugs have the potential to provide more effective and less toxic therapeutic alternatives. The approach employed in this study, which involves repurposing drugs through molecular docking and molecular dynamics, serves as a valuable tool for identifying novel drug candidates with distinct therapeutic uses. This methodology can contribute to reducing the attrition rate and expediting the process of drug discovery.

Comments:

The study you described focuses on the identification of potential allosteric inhibitors of Tropomyosin-receptor kinase A (TrkA), a protein associated with cancer development. The researchers conducted a comprehensive screening of 9,923 drugs from the ChEMBL database using molecular docking techniques to identify potential candidates for repurposing. Molecular docking is a computational method used to predict the binding affinity and orientation of small molecules within a protein's binding site. The top 49 candidates were further evaluated using MM-GBSA calculations, which provide insights into the binding energies of protein-ligand complexes.

Among the shortlisted candidates, delanzomib and tibalosin exhibited the most promising results in terms of docking scores and binding energies. These two compounds were subjected to extensive molecular dynamics simulations to assess the stability of their interactions with TrkA over a period of 200 nanoseconds. Molecular dynamics simulations are computational techniques used to study the behavior of molecules over time, providing valuable information about their dynamic interactions.

The stable interactions observed during the simulations indicate that delanzomib and tibalosin have the potential to serve as allosteric inhibitors of TrkA. Allosteric inhibitors modulate the activity of proteins by binding to sites other than the active site, offering a different approach to traditional enzyme inhibitors.

The findings suggest that delanzomib and tibalosin could be promising candidates for further experimental evaluation. If validated through experiments, these compounds could offer more effective and less toxic alternatives for cancer therapy. Moreover, the study highlights the importance of computational approaches, such as molecular docking and molecular dynamics simulations, in drug discovery and repurposing efforts. These methods can significantly expedite the process of identifying novel drug candidates, ultimately contributing to the development of targeted and efficient therapies for various diseases, including cancer.