Taming the ringmaster of the genome (PCNA): Phytomolecules for anticancer therapy against a potential non-oncogenic target

Abstract The proliferating cell nuclear antigen (PCNA) is a multipurpose nuclear protein in almost every form of life. It plays a significant role as a part of the mechanism for DNA replication and DNA repair process. Owing to its multi-functional role inside the cell, PCNA is often referred as the ringmaster of the genome or the maestro of the replication fork. PCNA was suggested for anticancer therapy as a potential non-oncogenic target. In this study, a set of bioactive molecules was screened to identify molecules that could effectively bind to the target site on PCNA and alter its protein-protein interactions. A combined computational approach consisting of molecular interactions, thermodynamics free energy estimations by the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations, conventional and steered MD simulations were utilized to identify potential inhibitors of PCNA. Our robust computational approach suggested two bioactive molecules, Hypericin and Pseudohypericin, from plant Hypericum perforatum as more potent inhibitors of PCNA than the standard co-crystallized inhibitor. These molecules could be developed as modulators of PCNA protein-protein interactions and effective anticancer drugs. These results however require validation by appropriate experimental studies.