Lignin-Derived Oligomers as Promising mTOR Inhibitors: Insights from Dynamics Simulations.

Area of Science:

• Biochemistry
• Computational Biology
• Drug Discovery

Background:

• The mammalian target of rapamycin (mTOR) pathway regulates critical cellular processes like growth and metabolism.
• Dysregulation of mTOR is implicated in diseases such as cancer and age-related conditions.
• Rapamycin, a natural antibiotic, is a key inhibitor of mTORC1, facilitating its study.

Purpose of the Study:

• To computationally investigate the interaction of mTOR with established inhibitors and novel lignin-derived oligomers.
• To assess the binding stability and dynamics of mTOR-ligand complexes using molecular simulations.

Main Methods:

• All-atom molecular dynamics simulations in explicit solvent.
• Analysis of root mean square deviation, root mean square fluctuation, hydrogen bonds, binding free energy, and principal component analysis.
• Utilized a high-performance computing platform for extensive simulations.

Main Results:

• All seven tested ligands, including five lignin-derived oligomers, demonstrated stable interactions with mTOR.
• Lignin-derived compounds exhibited binding stability comparable to or exceeding that of reference drugs (everolimus and rapamycin).
• Molecular dynamics revealed consistent and stable complex formation over the simulation period.

Conclusions:

• Lignin-derived oligomers represent a promising and sustainable scaffold for developing new mTOR inhibitors.
• Computational methods effectively evaluated the binding dynamics and stability of potential drug candidates.
• These findings support the exploration of natural polyphenols as a basis for novel therapeutic agents targeting the mTOR pathway.