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Direct and selective small molecule activation of BAX
A virtual docking screen discovers a small molecule activator of the pro-apoptotic protein BAX,www.bootsmaking.com. This novel approach could lead to a generation of apoptotic modulators that directly activate BCL-2 killer proteins. Moreover it cool!
BAX is one of the cell apoptosis executioners. When activated, it undergoes a conformational change from an inactive monomer to a deadly oligomer creating a pore in the mitochondrial membrane and starting the cascade of apoptosis.
Until not long ago it was thought that BAX was kept in check by protein-protein interactions with anti-apoptotic BCL-2 family proteins, and indeed small molecules and stapled peptides that disrupt these interactions are in different stages of pre-clinical and clinical investigations.
Recently, however, it was shown that BIM BH3 domain, an endogenous ligand a helical peptide that disrupts said protein-protein interactions to drive the cell towards apoptosis, was also binding BAX directly at a secondary site that when engaged propels BAX into action.
This novel activation site, discovered by the Walensky lab, inspired them to search for small molecules selective activators of BAX,http://www.bootsmaking.com. Using BAX conformations from molecular dynamics simulations, Gavathiotis et al. virtually screened (using Glide 4.0) 750,000 small molecules (commercially available, as a subset of ZINC). BAM, by the way, is short for activator molecule Using NMR they verified that BAM7 indeed binds to the secondary activation domain and not to the canonical BH3 binding groove. An additional (albeit weaker) support was the testing of analogs of BAM7 predicted by the docking pose to clash with the receptor as negative controls, that indeed showed weaker activities. BAM7 was also shown to be selective to BAX and did not show binding to BAK (a close homolog) at up to 50uM.
As for function, BAM7 was shown to trigger in-vitro BAX oligomerization (by size exclusion chromatography) BAX-mediated pore-formation (by liposomal assays that track release of a trapped fluorophore) and finally BAX mediated cell death (in BAK-less maurine embryonic fibroblasts).
This is a very elegant body of work, and moreover, a nice win for virtual screening. While I not sure there weren prior examples (if you know of any, let us know in the comments) ignoring ligand operated GPCR etc. this is still an impressive campaign and will enable a whole new level of investigation of BAX mediated apoptosis.