Extremely Tight Binding of a Ruthenium Complex to Glycogen Synthase Kinase 3

The Potential Role of Glycogen Synthase Kinase 3 Inhibitors as Amyotrophic Lateral Sclerosis Pharmacological Therapy

“…The great majority of GSK-3 inhibitors are small molecules from organic synthesis but also marine natural compounds have produced different interesting leads [61,62]. Some peptides and organometallic compounds have also been studied in the search of a safe and effective GSK-3 inhibitor with good pharmacokinetic profile [63,64].…”

Organometallics as Structural Scaffolds for Enzyme Inhibitor Design

“…With the metallopyridocarbazole serving as the pharmacophoric model, half-sandwich scaffolds (e.g., EA1, HB1052) or truly octahedral complexes (e.g., FL411, HB806) (Fig. 3) were developed [31][32][33][34][35][36][37][38][39][40][41][42]. For example, cyclopentadienyl-CO half-sandwich Organometallics as Structural Scaffolds for Enzyme Inhibitor Designcomplexes were identified as privileged lead structures for obtaining highly potent and selective inhibitors for the protein kinases GSK-3 and Pim-1 [31, 32, 34-36, 39, 41].…”

“…Currently, seven structures of ruthenium half-sandwich complexes with protein kinases are available in the protein databank, four with Pim-1 (2BZH, 2BZI, 2OI4, 2BZJ), one with Pim-2 (2IWI), one with GSK-3b (2JLD), and one with PAK-1 (3FY0) [31,36,37,39]. In addition, a cocrystal structure of an osmium half-sandwich complex with Pim-1 was published recently (3BWF) [38].…”

“…4a) bound to the ATPbinding site of GSK-3b (Fig. 4b), which is located in a deep cleft located between two lobes of the kinase domain [31]. NP549 forms several hydrogen bonds within the ATP-binding site of GSK-3b (Fig.…”

“…Overall, NP549 perfectly complements the shape of the ATP-binding site and the ruthenium center is not in direct contact with any amino acid residue of the active site. With a K i value of 5 pM or less, (R Ru ,R c )-NP549 is one of the most potent protein kinase inhibitors reported to date and by almost four orders of magnitude more potent than the related natural product staurosporine (IC 50 ¼ 180 nM at 100 mM ATP), demonstrating that this organoruthenium structure is a privileged scaffold for the design of GSK-3 inhibitors [31].…”