Pinoresinol as a Potential c-Myc Complex Modulator: An In Silico Study

Abstract

The c-Myc oncoprotein is a central regulator of oncogenic transcriptional programs that remains challenging to inhibit directly, necessitating strategies that target c-Myc–associated protein complexes rather than the protein alone. This study conducted an in silico evaluation of the natural biphenolic lignan pinoresinol as a potential modulator of the c-Myc–TBP–TAF1 (TATA-binding protein (TBP)- Multiple direct interactions of TBP with the MYC oncoprotein) transcriptional complex (PDB ID: 6E16). Prior to molecular docking, the protein structure was subjected to energy minimization using the AMBER ff14SB force field to optimize conformational stability and structural reliability; ligand preparation and docking were performed with standard, widely used tools (e.g., AutoDock Vina v1.1.2; visualization and interface analyses in UCSF Chimera/ChimeraX and SeamDock). Molecular docking and binding-interface analyses identified reproducible interactions within defined pockets P0, P1, and P2, with pocket P0 exhibiting the highest Drug Score of 0.82. Binding affinities ranged from −5.0 to −7.1 kcal/mol, which are consistent with moderate docking scores typical for small natural ligands. Across multiple ligand poses, LYS327, LYS310, and ASP209 emerged as consistent interaction hotspots, with LYS327 showing the most frequent contacts. Furthermore, in silico ADMET analysis predicted a high probability of cytotoxic inactivity (0.98), suggesting a favorable safety profile compared to traditional agents like vincristine. These results support a protein–protein interface-oriented approach and position pinoresinol as a promising lead scaffold for disrupting c-Myc–associated transcriptional regulation.