4bhz

Scaffold Focused Virtual Screening: Prospective Application to the Discovery of TTK InhibitorScaffold Focused Virtual Screening: Prospective Application to the Discovery of TTK Inhibitor

Structural highlights

4bhz is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.85Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TTK_HUMAN Phosphorylates proteins on serine, threonine, and tyrosine. Probably associated with cell proliferation. Essential for chromosome alignment by enhancing AURKB activity (via direct CDCA8 phosphorylation) at the centromere, and for the mitotic checkpoint.^[1]

Publication Abstract from PubMed

We describe and apply a scaffold-focused virtual screen based upon scaffold trees to the mitotic kinase TTK (MPS1). Using level 1 of the scaffold tree, we perform both 2D and 3D similarity searches between a query scaffold and a level 1 scaffold library derived from a 2 million compound library; 98 compounds from 27 unique top-ranked level 1 scaffolds are selected for biochemical screening. We show that this scaffold-focused virtual screen prospectively identifies eight confirmed active compounds that are structurally differentiated from the query compound. In comparison, 100 compounds were selected for biochemical screening using a virtual screen based upon whole molecule similarity resulting in 12 confirmed active compounds that are structurally similar to the query compound. We elucidated the binding mode for four of the eight confirmed scaffold hops to TTK by determining their protein-ligand crystal structures; each represents a ligand-efficient scaffold for inhibitor design.

Scaffold-Focused Virtual Screening: Prospective Application to the Discovery of TTK Inhibitors.,Langdon SR, Westwood IM, van Montfort RL, Brown N, Blagg J J Chem Inf Model. 2013 May 24;53(5):1100-12. doi: 10.1021/ci400100c. Epub 2013, May 14. PMID:23672464^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Jelluma N, Brenkman AB, van den Broek NJ, Cruijsen CW, van Osch MH, Lens SM, Medema RH, Kops GJ. Mps1 phosphorylates Borealin to control Aurora B activity and chromosome alignment. Cell. 2008 Jan 25;132(2):233-46. doi: 10.1016/j.cell.2007.11.046. PMID:18243099 doi:10.1016/j.cell.2007.11.046
↑ Langdon SR, Westwood IM, van Montfort RL, Brown N, Blagg J. Scaffold-Focused Virtual Screening: Prospective Application to the Discovery of TTK Inhibitors. J Chem Inf Model. 2013 May 24;53(5):1100-12. doi: 10.1021/ci400100c. Epub 2013, May 14. PMID:23672464 doi:10.1021/ci400100c

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OCA

[1] Jelluma N, Brenkman AB, van den Broek NJ, Cruijsen CW, van Osch MH, Lens SM, Medema RH, Kops GJ. Mps1 phosphorylates Borealin to control Aurora B activity and chromosome alignment. Cell. 2008 Jan 25;132(2):233-46. doi: 10.1016/j.cell.2007.11.046. PMID:18243099 doi:10.1016/j.cell.2007.11.046

[2] Langdon SR, Westwood IM, van Montfort RL, Brown N, Blagg J. Scaffold-Focused Virtual Screening: Prospective Application to the Discovery of TTK Inhibitors. J Chem Inf Model. 2013 May 24;53(5):1100-12. doi: 10.1021/ci400100c. Epub 2013, May 14. PMID:23672464 doi:10.1021/ci400100c

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