Design and anti-drug resistance research of novel PCNA-targeted inhibitors Based on network pharmacology and molecular docking

Proliferating cell nuclear antigen (PCNA) is crucial for maintaining genomic integrity and plays a significant role in cancer development and treatment resistance. Given the limitation that the current PCNA-targeted drug, AOH1996, is susceptible to inducing mutation resistance at the L47V site, this study introduces an innovative coupled drug design strategy based on a dual-ligand collaboration mechanism. By systematically analyzing the complementary interaction mechanism between AOH1996 and EGCG , the carboxylic acid group of AOH1996 was aminated and coupled with the phenolic hydroxyl group of EGCG using a flexible alkyl chain linker. This approach led to the construction of two candidate molecules, AL-1 (C 30 H 35 N 2 O 11 ) and AL-3 (C 29 H 31 NO 11 ), featuring dual active centers. This study presents a novel dual anti-drug resistance PCNA targeting strategy characterized by "structural coupling - functional synergy," offering a new molecular design paradigm to address the issue of drug resistance in single-target inhibitors. Nonetheless, the in vivo and in vitro activities of these candidates require validation through subsequent experiments.The findings of this study underscore the pivotal role of network pharmacology in the advancement of multi-target drug development and establish a theoretical basis for the creation of next-generation anti-cancer drugs that address structural drug resistance mechanisms.