Exploring structural diversity and dynamic stability of small-molecule PRMT5 inhibitors through machine learning-based QSAR and molecular modelling.

Protein arginine methyltransferase 5 (PRMT5) is a key epigenetic enzyme that catalyses symmetric arginine methylation on histone and non-histone proteins, influencing chromatin organisation, RNA splicing, and oncogenic signalling. Its overexpression and dependency in MTAP-deleted cancers such as glioblastoma, pancreatic adenocarcinoma, and non-small cell lung carcinoma highlight its therapeutic relevance. This study presents an integrative computational framework combining quantitative structure-activity relationship (QSAR) modelling, molecular docking, molecular dynamics (MD) simulations, and network pharmacology to identify potential PRMT5 inhibitors. The best QSAR models based on machine learning techniques used different fingerprint representations and algorithms to describe chemical structures; Random Forest models trained on PubChem and MACCS descriptor combinations provided the most accurate predictions. Analysis of consensus QSAR models identified two highly active PRMT5 inhibitor candidates (CHEMBL4539612 and CHEMBL4577464), with high affinity for binding (- 13.5 to - 13.7 kcal/mol) to the PRMT5 active site and interactions similar to those of the known clinical PRMT5 inhibitor ONAMETOSTAT. Molecular dynamics simulations showed that both candidate molecules-maintained stability throughout the PRMT5 catalytic cleft, due to consistent hydrogen bonding, compact conformations, and low negative binding free energy values determined by MM-GBSA calculations. Network pharmacology analysis indicated that PRMT5 and its interacting partners are mainly associated with histone arginine methylation and spliceosomal assembly, processes that are frequently dysregulated in MTAP-deficient cancers. These findings suggest CHEMBL4539612 and CHEMBL4577464 as promising scaffolds for the development of selective PRMT5 inhibitors in epigenetic cancer therapy.