Evodiamine and Rutaecarpine as Potential Anticancer Compounds: A Combined Computational Study

Area of Science:

• Computational Chemistry
• Molecular Pharmacology
• Natural Products Chemistry

Background:

• Evodiamine (EVO) and rutaecarpine (RUT) are key bioactive compounds from the traditional Chinese herb Evodia rutaecarpa.
• These compounds have demonstrated potential therapeutic properties, necessitating detailed mechanistic studies.

Purpose of the Study:

• To elucidate the anticancer mechanisms of EVO and RUT at a molecular level.
• To investigate their interaction with the topoisomerase 1 (TOP1) enzyme, a key target in cancer therapy.
• To explore the structure-activity relationship between EVO, RUT, and TOP1.

Main Methods:

• Density functional theory (DFT) calculations (B3LYP/6-311++G (d, p)) for molecular geometry optimization.
• Natural Population Analysis (NPA), frontier molecular orbital (FMO) analysis, and molecular electrostatic potential (MEP) mapping.
• Molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations against TOP1.

Main Results:

• DFT calculations provided optimized molecular geometries and electronic properties for EVO and RUT.
• Molecular docking revealed that EVO and RUT can inhibit TOP1 by intercalating into the DNA-binding site, forming a ternary complex.
• MD simulations confirmed the stability of the TOP1−DNA−ligand complex, with EVO showing stronger binding affinity than RUT.

Conclusions:

• EVO and RUT are potential inhibitors of topoisomerase 1, suggesting a mechanism for their antitumor activity.
• The study elucidates the structure-activity relationship and molecular antitumor mechanisms of EVO and RUT.
• EVO and RUT represent promising candidates for the development of novel anticancer therapeutics.