Design of Novel PI4KIIIβ Inhibitors Based on QSAR, Molecular Docking, and Molecular Dynamics Simulations

Abstract

Phosphatidylinositol 4‐kinase IIIβ (PI4KIIIβ) is a key enzyme responsible for catalyzing the production of phosphatidylinositol 4‐phosphate (PI4P). It plays a central role in regulating physiological and pathological processes, including membrane transport, signal transduction, and pathogen infection. Recently, aberrant activation of PI4KIIIβ has been identified in multiple malignancies, including colorectal cancer and glioma. This dysregulation promotes tumor cell survival through the modulation of critical signaling pathways and autophagy. This establishes PI4KIIIβ as a promising target for anti‐tumor therapy. In this study, a stable Topomer CoMFA ( q 2 = 0.686, r 2 = 0.966) and HQSAR ( q 2 = 0.729 , r 2 = 0.968) models were constructed based on 43 PI4KIIIβ inhibitors with clear biological activity. Both models exhibit satisfactory internal stability and external predictive capabilities. The QSAR results were used to virtually screen the ZINC20 database, and 17 novel compounds with potential high inhibitory activity were designed. Molecular docking and molecular dynamics simulations further verify the stability and feasibility of binding interactions between these new compounds and PI4KIIIβ target proteins. This work not only provides a reliable QSAR model for efficient screening of anti‐tumor drugs, but also lays a solid theoretical foundation for the structural design and optimization of novel PI4KIIIβ inhibitors, highlighting their potential value in drug discovery and development.