Computational Insights Into Effects of External Electric Fields on the Reaction Mechanism Involved in the Synthesis of Hymecromone; DFT and Molecular Dynamics Analysis

Abstract

ABSTRACT We investigated the effect and influence of an external electric field on the synthesis of hymecromone from 1,3‐diphenol and acidified ethyl acetoacetate and evaluated its potential as a breast cancer inhibitor using molecular electronics density transfer (MEDT) at the ωB97XD/6‐311++G(d,p) level of theory, along with molecular docking, molecular mechanics, the generalized Born model, and solvent accessibility (MM/GBSA), as well as molecular dynamics (MD) simulations. Exploration of the potential energy surface (PES) revealed two reaction pathways ( a and b ), with product R_07 predominantly formed via the more favorable channel‐a result that aligns well with experimental observations. The oriented external electric field (OEEF) analysis identified coordinates ( x = −50/ x = −100, y = −100 V/nm) that act as catalysts for the reaction, while the OEEF acts as an inhibitor when oriented along the y ‐axis with a value of 50 V/nm. The MD simulations of the hymecromone–1g50 complex revealed the sustained presence of intermolecular hydrogen bonds and hydrophobic interactions between the ligand and critical residues of the estrogen receptor (ER) throughout the 100 ns simulation period. This lead compound maintained a stable binding conformation and consistently occupied the receptor's active site. Consequently, as a potential ER antagonist, the compound examined in this study may serve as a valuable reference for future experimental research targeting breast cancer.