Phytochemical‐Based Drug Discovery for Breast Cancer: Combining Virtual Screening and Molecular Dynamics to Identify Novel Therapeutics

Maternal embryonic leucine zipper kinase (MELK), a pivotal signaling protein, plays a crucial role in various physiological processes, such as cell growth, survival, and differentiation. There is currently a growing interest in MELK as a promising therapeutic target for multiple cancers, including triple-negative breast cancer (TNBC). Exploring MELK as a target offers a prospective strategy to impede cancer progression and enhance the efficacy of conventional anticancer therapies. In this study, we employed a multistep docking procedure to evaluate the anticancer potential of phyto-compounds from the NPACT and PhytoHub databases targeting the MELK protein. A collection of 23 740 compounds underwent hierarchical multistep docking, accompanied by an analysis of binding interactions. The extensive analysis identified five compounds (PHUB000697, PHUB002010, NPACT00373, PHUB002005, and PHUB001739) as potent inhibitors of the MELK protein, exhibiting docking scores lower than -11 Kcal/mol, that is, -12.90, -12.00, -11.23, -11.19, and -11.09 Kcal/mol, respectively. PHUB000697 exhibited very crucial interactions with Gly20, Lys40, Cys89, and Glu93 (2.74 Å). To evaluate the stability of protein-ligand interactions in dynamic states, 100 ns molecular dynamics (MD) simulations were conducted using the entire trajectory, revealing a substantial binding affinity for all identified compounds toward the MELK protein. Consequently, these five compounds emerge as promising candidates for future drug development targeting the MELK protein in treating TNBC. However, experimental assessment is essential to understand the molecular interaction mechanisms better. We are aiming to report a few in vitro and in vivo studies on these compounds to validate the computational results.