In Silico Exploration of Anti‐Cancer Phytochemicals as Novel Inhibitors of LRRK2 via the WDR Domain

Abstract LRRK2 serves as a significant oncogenic driver in multiple malignancies, including glioblastoma, lung, breast, and ovarian cancers. It enhances cancer cell growth, metastasis, and survival by modulating critical signaling pathways, including MET, p53, and JNK. The WD40‐repeat (WDR) domain of LRRK2 is a crucial protein–protein interaction region required for regulating oncogenic signaling pathways. The current research examines the inhibitory ability of 104 phytochemicals obtained from anticancer plants against the WDR domain of LRRK2 through in silico experiments that include drug‐likeness, molecular docking, molecular dynamics simulations, and ADMET profiling. Ellagic acid and cucurbitacin B exhibited enhanced binding affinities (−9.58 and −8.46 kcal/mol, respectively) compared to the reference compound MLi‐2‐NC (−3.16 kcal/mol). Both compounds showed no ability to block the hERG channel, were non‐mutagenic, and had moderate intestinal absorption. Molecular dynamics simulations indicated durable binding interactions, with cucurbitacin B displaying the strongest binding free energy (−25.69 kcal/mol) and persistent protein–ligand interactions, whereas ellagic acid exhibited consistent but comparatively weaker interactions (−11.84 kcal/mol). Here, ellagic acid and cucurbitacin B are identified as promising for further development as agents that can modulate LRRK2‐driven carcinogenic pathways. These findings offer compelling justification for experimental validation.