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. The extensive analysis identified five compounds (PHUB000697, PHUB002010, NPACT00373, PHUB002005, and PHUB001739) as potent inhibitors of the MELK protein, exhibiting a docking scores lower than -11 Kcal/mol i.e. -12.90, -12.00, -11.23, -11.19, -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 towards the MELK protein. We are aiming to report few in vitro and in vivo studies on these compounds to validate the computational results.