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

Remarkably, two of these are already associated with cancer therapy, namely, lenalidomide and thalidomide, which induce apoptosis and are used in the treatment of multiple myeloma and myelodysplastic syndromes. 46, 47 Thalidomide and lenalidomide are structural analogs of the rhodanine derivative, BH3I-1, developed by Degterev et al, 48 which binds the BH3 binding groove of Mcl-1 with micromolar affinity. Of the top 10 drugs, at least three have dopaminergic and serotonergic activity. Dolasetron is a serotonergic and dopaminergic antagonist used against nausea, droperidol is an antidopaminergic antipsychotic, mazindol is a catecholamine reuptake inhibitor and a central nervous system (CNS) stimulant, trazodone is a serotonergic antagonist and reuptake inhibitor, and nebivolol is a β1-adrenergic receptor blocker with significant dopaminergic pharmacology. 49 (Structurally, trazodone is of particular interest as it ranks first on average.) Finally, three other drugs do not seem to be linked with serotonergic and dopaminergic activity. Azelastine is a second-generation H1 histamine receptor antagonist, deferasirox is an oral iron chelator used to reduce chronic iron overload, and torsemide is a pyridine-sulfonylurea-type loop diuretic mainly used in the management of edema associated