<i>In Silico</i> Design of a Gallic Acid-based Conjugate Targeting Human Mitochondrial PRDX5: A DFT, Docking, Dynamics and ADMET Analysis

Abstract

Oxidative stress is a critical driver of cancer progression, and modulation of mitochondrial redox balance represents a promising therapeutic strategy. Here, we present a comprehensive computational investigation of gallic acid derivatives — including alkyl gallates, chitosan–gallic acid conjugates (CG1: amide-linked, CG2: ester-linked), glucose–gallic acid (GG) and epigallocatechin gallate (EGCG) — targeting the mitochondrial antioxidant enzyme peroxiredoxin 5 (PRDX5), a novel approach not previously reported. The workflow combined density functional theory (DFT)-based antioxidant mechanism analysis (HAT, SET-PT, SPLET), molecular docking, 500 ns molecular dynamics simulations and ADMET profiling. Our results revealed that EGCG, CG1–CG2 and GG exhibited superior stability and activity toward PRDX5 compared with alkyl gallates. EGCG formed the most stable complex but showed limited absorption due to its high polarity, whereas methyl gallate (MG) displayed a favorable ADMET profile, supporting its role as an auxiliary linker. Notably, GG aligned strongly with the SPLET mechanism in polar media, attributed to its higher acidity and favorable deprotonation, highlighting potential for smart, targeted antioxidant applications. As a theoretical extension, we propose a hypothetical construct (EGM_OxMito-1): a redox-responsive EGCG–MG conjugate linked via a thioketal bond, encapsulated in PLGA–PEG nanoparticles, and functionalized with triphenylphosphonium (TPP + ) and GG for mitochondrial and cancer-cell targeting. This design is entirely conceptual, intended to illustrate a possible strategy for ROS-triggered release and PRDX5 inhibition, and to provide a forward-looking framework for future experimental validation in oxidative stress-based cancer therapy.