Virtual screening for potential inhibitors of Mcl-1 conformations sampled by normal modes, molecular dynamics, and nuclear magnetic resonance

Glantz-Gashai, Yitav; Meirson, Tomer; Reuveni, Eli; Samson, Abraham O

Since Mcl-1 is located inside the cytosol, the potential drugs must be able to cross the cell membrane. For most FDA-approved drug candidates listed here, some form of membrane crossing has been reported. For the lead-like compounds, however, cellular penetration data are unavailable, and only estimates based on the predicted octanol/water partition coefficient (LogP) are available. 50 serotonergic, dopaminergic, and histaminergic hypothesis Serotonin, dopamine, and histamine regulate cell proliferation, migration, maturation, and apoptosis in a variety of cell types, including lung, kidney, endothelial cells, mast cells, neurons, and astrocytes. 51, 52 Some of the potential Mcl-1 ligands presented here are serotonergic, dopaminergic, and histaminergic modulators (ie, ergotamine, paliperidone, lurasidone, and risperidone) and share structural similarity with serotonin, dopamine, and histamine. We hypothesize that serotonin, dopamine, histamine, and Mcl-1 modulation are associated. Such a coincidence is further supported by the vicious cycle of depression, anxiety, and cancer, which are both characterized by abnormally low levels of serotonin and dopamine. 53 Drug Design, Development and Therapy 2017:11 submit your manuscript | www.dovepress.com Dovepress Dovepress 1812 glantz-gashai et al