Computational Design of New 3‐Phenoxy β‐Lactams as Tubulin Polymerization Inhibitors for Breast Cancer Therapy

Abstract

Abstract The objective of this study is to contribute to the fight against cancer. The World Health Organization predicts a 70% increase in new cancer cases in developing countries. Given their critical role in drug discovery, computational approaches were used to design 3‐phenoxy β‐lactams as potential inhibitors of tubulin polymerization, with several derivatives analyzed for their activity against MCF‐7 breast cancer cells. The most robust H‐QSAR model was characterized by the following statistical parameters: R 2 train = 0.905, Q 2 cv = 0.749, SEE = 0.301, R 2 pred = 0.504, and R 2 test = 0.827. These values demonstrate the model's strong predictive capability, confirming its effectiveness in designing new compounds targeting tubulin. Six new molecules with enhanced activity were proposed, with molecular docking assessing their potential as tubulin polymerization inhibitors. The compounds showed strong interactions with targeted receptors and high binding affinity. The potential of three receptor–ligand complexes was evaluated through molecular dynamics simulations. Trajectory analysis and binding free energy (MMPBSA) confirmed their stability within the protein's active site. Pharmacokinetic and ADME‐Tox studies supported their drug‐like potential. These findings highlight the potential efficacy of the three new molecules as anticancer agents, encouraging further in vitro and in vivo studies to validate their therapeutic potential.