Pim + Ru organo metallics
Pim + Ru organo metallics: Human Pim1 in complex with three organometallic Ru half-sandwich complexes
PDB Code: 2BZH, 2BZI, 2BZJ
With this study we were aiming to extend small molecule chemical space with kinetically inert metal complexes allowing to access areas in binding pockets that may not be easily reachable with purely organic scaffolds. To explore this we determined the structure of ruthenium half-sandwich complexes ((R)- 5 , (S)- 6 and EA72E2 (which has a substituted cyclopentadiene ring)) that were found to be extremely potent ( IC 50 up to 200 pM) and selective inhibitors for Pim-1 kinase. These inhibitors are based on the non-selective natural product staurosporine. In these complexes the bidentate staurosporine pyridocarbazole moiety coordinates a Ru atom together with a CO and cyclopentadiene ligand forming a pseudo-octahedral complex. The determined structures showed that these inhibitors in general closely mimic the binding mode of the staurosporine parent compound. All three inhibitors fit tightly into the binding pocket showing a very nice shape complementarity and form a number of hydrophobic interactions with Pim-1 residues.
Overlaying all three crystal structures showed that the maleimide group, the cyclopentadienyl ring, and the CO group are in very similar positions. The main differences are mainly limited to a 180° flipped pyridocarbazole moiety. The maleimide group of ( R )- 5 forms an additional water mediated hydrogen bond not present in the ( S )- 6 complex. In addition, the hydroxyl group at the indole moiety in ( S )- 6 is involved in hydrogen bonds to two ordered water molecules, explaining at least in part the approximately 10-fold lower IC 50 of ( S )- 6 compared to ( R )- 5 . The presence of an OH group at the indole ring leads also to a slight rotation of the pyridocarbazole moiety.
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