Virtual screening of compounds for the development of thyroid hormone analogues for potential application in cardiac...

Area of Science:

• Biochemistry
• Computational Biology
• Cardiovascular Research

Background:

• Cardiovascular diseases are the leading cause of death globally.
• Limited regeneration of adult cardiac tissue hinders treatment options.
• Thyroid hormones, like tri-iodothyronine (T3), can promote cardiomyocyte proliferation via thyroid hormone receptor alpha (TRα).

Purpose of the Study:

• To identify novel agonists for the thyroid hormone receptor alpha (TRα) using a multi-level virtual screening approach.
• To develop and validate a computational framework for drug discovery in cardiac regeneration.
• To find potential therapeutic agents that can stimulate heart tissue repair.

Main Methods:

• A hierarchical virtual screening pipeline integrating Molecular Mechanics (MM), Quantum Mechanics (QM), and QM/MM calculations.
• Analysis of reactivity using the Fukui function to understand protein-ligand interactions.
• Screening of over 412 million compounds from the ZINC15 database, followed by filtering, pharmacophore matching, docking, and binding affinity evaluation.

Main Results:

• The screening process identified 568 candidate compounds from an initial pool of millions.
• Two compounds, including the drug Cetraxate, demonstrated favorable interaction energies and reactivity patterns similar to T3.
• These candidates show mechanistically supported potential as TRα agonists.

Conclusions:

• A rigorous, multi-scale computational framework was established for identifying TRα agonists.
• Two promising TRα agonist candidates were identified for future experimental validation.
• This research offers a novel computational strategy for advancing cardiac regeneration therapies.