4bi0 Citations

Scaffold-Focused Virtual Screening: Prospective Application to the Discovery of TTK Inhibitors.

OpenAccess logo J Chem Inf Model (2013)
Related entries: 4bhz, 4bi1, 4bi2

Cited: 8 times
EuropePMC logo PMID: 23672464


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.

Reviews citing this publication (2)

  1. Hierarchical virtual screening approaches in small molecule drug discovery. Kumar A, Zhang KY. Methods 71 26-37 (2015)
  2. Biomaterial-based scaffolds--current status and future directions. Garg T, Goyal AK. Expert Opin Drug Deliv 11 767-789 (2014)

Articles citing this publication (6)

  1. Discovery of novel small-molecule inhibitors of BRD4 using structure-based virtual screening. Vidler LR, Filippakopoulos P, Fedorov O, Picaud S, Martin S, Tomsett M, Woodward H, Brown N, Knapp S, Hoelder S. J. Med. Chem. 56 8073-8088 (2013)
  2. Structure-based design of orally bioavailable 1H-pyrrolo[3,2-c]pyridine inhibitors of mitotic kinase monopolar spindle 1 (MPS1). Naud S, Westwood IM, Faisal A, Sheldrake P, Bavetsias V, Atrash B, Cheung KM, Liu M, Hayes A, Schmitt J, Wood A, Choi V, Boxall K, Mak G, Gurden M, Valenti M, de Haven Brandon A, Henley A, Baker R, McAndrew C, Matijssen B, Burke R, Hoelder S, Eccles SA, Raynaud FI, Linardopoulos S, van Montfort RL, Blagg J. J. Med. Chem. 56 10045-10065 (2013)
  3. Inhibitor ranking through QM based chelation calculations for virtual screening of HIV-1 RNase H inhibition. Poongavanam V, Steinmann C, Kongsted J. PLoS ONE 9 e98659 (2014)
  4. A unique hinge binder of extremely selective aminopyridine-based Mps1 (TTK) kinase inhibitors with cellular activity. Kusakabe K, Ide N, Daigo Y, Itoh T, Yamamoto T, Kojima E, Mitsuoka Y, Tadano G, Tagashira S, Higashino K, Okano Y, Sato Y, Inoue M, Iguchi M, Kanazawa T, Ishioka Y, Dohi K, Kido Y, Sakamoto S, Ando S, Maeda M, Higaki M, Yoshizawa H, Murai H, Nakamura Y. Bioorg. Med. Chem. 23 2247-2260 (2015)
  5. Discovery of new [Formula: see text] proteasome inhibitors using a knowledge-based computational screening approach. Mehra R, Chib R, Munagala G, Yempalla KR, Khan IA, Singh PP, Khan FG, Nargotra A. Mol. Divers. 19 1003-1019 (2015)
  6. Bioisosteres and Scaffold Hopping in Medicinal Chemistry. Brown N. Mol Inform 33 458-462 (2014)