Phenanthrenes as anti-liver cancer agents: A computational pipeline to tubulin inhibition.

The rising incidence of liver cancer highlights the urgent need for novel therapies targeting crucial molecular mediators such as tubulin, a key protein involved in cancer cell proliferation. This study aims to address this need through a robust pipeline combining QSAR, molecular docking, dynamics, and ADME to identify new promising anti-liver-cancer agents, with a focus on virtual screening of purchasable Aldrich® Market Select phenanthrene analogs. A QSAR model with 92.7 % predictive accuracy highlighted HeavyAtomCount and Chi1n as pivotal structural descriptors correlating with anti-proliferative activity in HepG2 cells. Subsequently, QSAR-based virtual screening enabled the identification of top candidates based on their anti-proliferative potential. Virtual screening via molecular docking prioritized compound 31, which exhibited exceptional binding affinity (-8.684 kcal/mol) at tubulin's colchicine site. ADME profiling confirmed favorable pharmacokinetics and low BBB permeability for lead candidates. Molecular dynamics (MD) simulations (200 ns) further validated compound 31's stability, indicative of a tightly bound conformation. By integrating QSAR, docking, ADME, and MD, this work establishes a computationally rigorous pipeline for anticancer drug discovery, offering phenanthrene-based scaffolds as candidates for in vitro testing. These results not only elucidate structure-activity principles for tubulin inhibition but also provide a pipeline for accelerating drug discovery, especially novel anticancer agents.