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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 53 1100-12 (2013)
Related entries: 4bhz, 4bi1, 4bi2

Cited: 17 times
EuropePMC logo PMID: 23672464

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.

Articles - 4bi0 mentioned but not cited (1)

  1. 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 53 1100-1112 (2013)


Reviews citing this publication (3)

  1. Biomaterial-based scaffolds--current status and future directions. Garg T, Goyal AK. Expert Opin Drug Deliv 11 767-789 (2014)
  2. Hierarchical virtual screening approaches in small molecule drug discovery. Kumar A, Zhang KY. Methods 71 26-37 (2015)
  3. Advances in the Development of Shape Similarity Methods and Their Application in Drug Discovery. Kumar A, Zhang KYJ. Front Chem 6 315 (2018)

Articles citing this publication (13)

  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. Bioisosteres and Scaffold Hopping in Medicinal Chemistry. Brown N. Mol Inform 33 458-462 (2014)
  4. Chemoinformatics-based enumeration of chemical libraries: a tutorial. Saldívar-González FI, Huerta-García CS, Medina-Franco JL. J Cheminform 12 64 (2020)
  5. Computational Screening of Natural Compounds for Identification of Potential Anti-Cancer Agents Targeting MCM7 Protein. Alshahrani MY, Alshahrani KM, Tasleem M, Akeel A, Almeleebia TM, Ahmad I, Asiri M, Alshahrani NA, Alabdallah NM, Saeed M. Molecules 26 5878 (2021)
  6. Identification of potential antivirals against SARS-CoV-2 using virtual screening method. Rahman MR, Banik A, Chowdhury IM, Sajib EH, Sarkar S. Inform Med Unlocked 23 100531 (2021)
  7. 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)
  8. LBVS: an online platform for ligand-based virtual screening using publicly accessible databases. Zheng M, Liu Z, Yan X, Ding Q, Gu Q, Xu J. Mol Divers 18 829-840 (2014)
  9. 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)
  10. Discovery of new Mycobacterium tuberculosis 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)
  11. Identification of New Mycobacterium tuberculosis Proteasome Inhibitors Using a Knowledge-Based Computational Screening Approach. Almeleebia TM, Shahrani MA, Alshahrani MY, Ahmad I, Alkahtani AM, Alam MJ, Kausar MA, Saeed A, Saeed M, Iram S. Molecules 26 2326 (2021)
  12. Identification of potential inhibitory analogs of metastasis tumor antigens (MTAs) using bioactive compounds: revealing therapeutic option to prevent malignancy. Banik A, Ahmed SR, Sajib EH, Deb A, Sinha S, Azim KF. Mol Divers 26 2473-2502 (2022)
  13. Synthesis and profiling of a 3-aminopyridin-2-one-based kinase targeted fragment library: Identification of 3-amino-5-(pyridin-4-yl)pyridin-2(1H)-one scaffold for monopolar spindle 1 (MPS1) and Aurora kinases inhibition. Fearon D, Westwood IM, van Montfort RLM, Bayliss R, Jones K, Bavetsias V. Bioorg Med Chem 26 3021-3029 (2018)


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