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G. Atilla-Gocumen, L. Di Costanzo, E. Meggers ^[1]

J Biol Inorg Chem (2011)

DOI 10.1007/s00775-010-0699-x

Introduction

The development of pharmaceutical drugs and chemical probes is predominantly focused on organic compounds. However, studies suggest that organic chemical space is limited, with a high degree of structural similarity across known molecules. To access novel chemical space, this research explores the use of substitutionally inert metal complexes as unique scaffolds for enzyme inhibitors. Metals like ruthenium can form stable, structurally diverse complexes that are not accessible with purely carbon-based chemistry. The organometallic half-sandwich ruthenium complex DW12 is a prime example, demonstrating potent and selective inhibition of the serine/threonine kinase Glycogen Synthase Kinase 3β (GSK-3β), a target with implications in cancer and neurodegenerative diseases. This paper details the crystal structure of (R)-DW12 bound to GSK-3β to elucidate its unique binding mode.

Key Interactions of (R)-DW12 with GSK-3β

The interactions between (R)-DW12 and GSK-3β fall into two major categories:

1. Hydrogen-bonding interactions (mostly with the hinge region)

2. Hydrophobic interactions (across both lobes and the glycine-rich loop)

Hydrogen-Bonding Interactions

(R)-DW12 forms three major hydrogen bonds with the hinge region of GSK-3β: Maleimide NH with the Asp133 carbonyl, Val135 NH interacting with Maleimide carbonyl and Indole OH which is interacting with Val135 carbonyl group.

Hydrophobic Interactions

The complex is tightly packed via numerous hydrophobic interactions with residues from both lobes, including Ile62, Val70, Ala83, Leu132, Val110, and Leu188.

Interaction with the Glycine rich loop

A distinctive feature is the interaction between the metal-coordinated CO ligand of (R)-DW12 and the glycine-rich loop (residues Ile62, Gly63, Phe67, Val70). The perpendicular orientation of the CO ligand relative to the planar pyridocarbazole heterocycle allows it to fit into a small hydrophobic pocket formed by the loop. This induces a "closed" conformation of the loop, where Phe67 packs closely against the inhibitor. This interaction is uncommon for most organic GSK-3β inhibitors, which typically exhibit an "open" glycine-rich loop conformation.

Within the hinge region, DW12 forms three canonical hydrogen bonds: the maleimide NH donates to Asp133, a carbonyl accepts from Val135, and the indole OH forms an additional bond with Val135. Numerous hydrophobic contacts stabilize the complex across both lobes.

Conclusion

The structure demonstrates that the ruthenium center serves a purely structural role, organizing the ligand geometry to enable unique interactions not accessible to organic scaffolds. The tight packing and specific interaction with the glycine-rich loop via the CO ligand are crucial for the high potency and selectivity of DW12 for GSK-3β, Pim-1, and Pim-2 kinases. This work highlights the potential of organometallic complexes to explore novel chemical space for designing selective kinase inhibitors.

References

1. ↑ Atilla-Gokcumen GE, Di Costanzo L, Meggers E. Structure of anticancer ruthenium half-sandwich complex bound to glycogen synthase kinase 3beta. J Biol Inorg Chem. 2010 Sep 7. PMID:20821241 doi:10.1007/s00775-010-0699-x