4BI2

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

Summary for 4BI2

• Entry DOI: 10.2210/pdb4bi2/pdb
• Related: 4BHZ 4BI0 4BI1
• Descriptor: DUAL SPECIFICITY PROTEIN KINASE TTK, 1,2-ETHANEDIOL, 2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL, ... (5 entities in total)
• Functional Keywords: transferase, mitosis
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 36736.01

Authors

Langdon, S.R.,Westwood, I.M.,van Montfort, R.L.M.,Brown, N.,Blagg, J. (deposition date: 2013-04-09, release date: 2013-05-22, Last modification date: 2023-12-20)

Primary citation

Langdon, S.R.,Westwood, I.M.,Van Montfort, R.L.M.,Brown, N.,Blagg, J.
Scaffold-Focused Virtual Screening: Prospective Application to the Discovery of Ttk Inhibitors.
J.Chem.Inf.Model, 53:1100-, 2013

PubMed Abstract: 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.

PubMed: 23672464
DOI: 10.1021/CI400100C

Experimental method

X-RAY DIFFRACTION (3.11 Å)