Identification of novel MEK1 inhibitors by pharmacophore and docking based virtual screening

Mitogen-activated protein kinase/mitogen-activated protein kinase kinase1 plays a key role in the Ras/Raf/MEK/ERK signaling pathway associated with cell growth, differentiation and development. In an effort to identify novel mitogen-activated protein kinase kinase1 inhibitors, an efficient multistep virtual screening approach was presented, including ligand-based pharmacophore (Hypo1) screening, physicochemical property filtering, and validated optimal docking analysis. Finally, six compounds were purchased and tested for their inhibitory activities in kinetics studies and cellular assays. Among them, compound M4 exhibited potent inhibition against mitogen-activated protein kinase kinase1 (IC50 = 3.5 μM) and modest proliferation inhibition in human HT-29 colon tumor line (IC50 = 13.6 μM) and human melanoma A375 cell line (IC50 = 16.2 μM). Taken together, our virtual screening might be useful for the mitogen-activated protein kinase kinase1 inhibitor research and M4 represents a new scaffold deserving further structural optimization for the treatment of mitogen-activated protein kinase kinase1-associated cancers. A ligand-based pharmacophore of MEK1 inhibitors was constructed and validated, then used to screen the SPECS compound library combined with optimal molecular docking (Glide XP), followed by biochemical and cellular assays.