What is the term used for small molecules that bind to different regions of a binding site?

1. Stockwell B.R. Exploring biology with small organic molecules. Nature. 2004;432:846–854. doi: 10.1038/nature03196. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

2. Hoelder S., Clarke P.A., Workman P. Discovery of small molecule cancer drugs: Successes, challenges and opportunities. Mol. Oncol. 2012;6:155–176. doi: 10.1016/j.molonc.2012.02.004. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

3. Lipinski C.A., Lombardo F., Dominy B.W., Feeney P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 1997;23:3–25. doi: 10.1016/S0169-409X(96)00423-1. [PubMed] [CrossRef] [Google Scholar]

4. Daniels D.L., Riching K.M., Urh M. Monitoring and deciphering protein degradation pathways inside cells. Drug Discov. Today Technol. 2019;31:61–68. doi: 10.1016/j.ddtec.2018.12.001. [PubMed] [CrossRef] [Google Scholar]

5. Scott D.E., Bayly A.R., Abell C., Skidmore J. Small molecules, big targets: Drug discovery faces the protein–protein interaction challenge. Nat. Rev. Drug Discov. 2016;15:533–550. doi: 10.1038/nrd.2016.29. [PubMed] [CrossRef] [Google Scholar]

6. Wagner B.K., Schreiber S.L. The Power of Sophisticated Phenotypic Screening and Modern Mechanism-of-Action Methods. Cell Chem. Biol. 2016;23:3–9. doi: 10.1016/j.chembiol.2015.11.008. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

7. Wagner B.K. The resurgence of phenotypic screening in drug discovery and development. Expert Opin. Drug Discov. 2016;11:121–125. doi: 10.1517/17460441.2016.1122589. [PubMed] [CrossRef] [Google Scholar]

8. Johannessen C.M., Clemons P.A., Wagner B.K. Integrating phenotypic small-molecule profiling and human genetics: The next phase in drug discovery. Trends Genet. 2015;31:16–23. doi: 10.1016/j.tig.2014.11.002. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

9. Jang B.S. MicroSPECT and MicroPET Imaging of Small Animals for Drug Development. Toxicol. Res. 2013;29:1–6. doi: 10.5487/TR.2013.29.1.001. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

10. Ashburn T.T., Thor K.B. Drug repositioning: Identifying and developing new uses for existing drugs. Nat. Rev. Drug Discov. 2004;3:673–683. doi: 10.1038/nrd1468. [PubMed] [CrossRef] [Google Scholar]

11. Brown D.G., Boström J. Where Do Recent Small Molecule Clinical Development Candidates Come from? J. Med. Chem. 2018;61:9442–9468. doi: 10.1021/acs.jmedchem.8b00675. [PubMed] [CrossRef] [Google Scholar]

12. Lombardino J.G., Lowe J.A. The role of the medicinal chemist in drug discovery—Then and now. Nat. Rev. Drug Discov. 2004;3:853–862. doi: 10.1038/nrd1523. [PubMed] [CrossRef] [Google Scholar]

13. Stocks M. Chapter 3—The small molecule drug discovery process—From target selection to candidate selection. In: Ganellin R., Roberts S., Jefferis R., editors. Introduction to Biological and Small Molecule Drug Research and Development. Elsevier; Oxford, UK: 2013. pp. 81–126. [CrossRef] [Google Scholar]

14. Mohs R.C., Greig N.H. Drug discovery and development: Role of basic biological research. Alzheimer’s Dement. Transl. Res. Clin. Interv. 2017;3:651–657. doi: 10.1016/j.trci.2017.10.005. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

15. Carnero A. High throughput screening in drug discovery. Clin. Transl. Oncol. 2006;8:482–490. doi: 10.1007/s12094-006-0048-2. [PubMed] [CrossRef] [Google Scholar]

16. Singh M., Tam B., Akabayov B. NMR-Fragment Based Virtual Screening: A Brief Overview. Molecules. 2018;23:233. doi: 10.3390/molecules23020233. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

17. Erlanson D.A., Fesik S.W., Hubbard R.E., Jahnke W., Jhoti H. Twenty years on: The impact of fragments on drug discovery. Nat. Rev. Drug Discov. 2016;15:605–619. doi: 10.1038/nrd.2016.109. [PubMed] [CrossRef] [Google Scholar]

18. Moitessier N., Pottel J., Therrien E., Englebienne P., Liu Z., Tomberg A., Corbeil C.R. Medicinal Chemistry Projects Requiring Imaginative Structure-Based Drug Design Methods. Acc. Chem. Res. 2016;49:1646–1657. doi: 10.1021/acs.accounts.6b00185. [PubMed] [CrossRef] [Google Scholar]

19. Anderson A.C. The Process of Structure-Based Drug Design. Chem. Biol. 2003;10:787–797. doi: 10.1016/j.chembiol.2003.09.002. [PubMed] [CrossRef] [Google Scholar]

20. Ou-Yang S.-S., Lu J.-Y., Kong X.-Q., Liang Z.-J., Luo C., Jiang H. Computational drug discovery. Acta Pharmacol. Sin. 2012;33:1131–1140. doi: 10.1038/aps.2012.109. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

21. Schneider P., Walters W.P., Plowright A.T., Sieroka N., Listgarten J., Goodnow R.A., Fisher J., Jansen J.M., Duca J.S., Rush T.S., et al. Rethinking drug design in the artificial intelligence era. Nat. Rev. Drug Discov. 2020;19:353–364. doi: 10.1038/s41573-019-0050-3. [PubMed] [CrossRef] [Google Scholar]

22. Mullard A. A snapshot of lead-generation strategies. Nat. Rev. Drug Discov. 2018;17:534. doi: 10.1038/nrd.2018.129. [PubMed] [CrossRef] [Google Scholar]

23. Corsello S.M., Bittker J.A., Liu Z., Gould J., McCarren P., Hirschman J.E., Johnston S.E., Vrcic A., Wong B., Khan M., et al. The Drug Repurposing Hub: A next-generation drug library and information resource. Nat. Med. 2017;23:405–408. doi: 10.1038/nm.4306. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

24. Goodnow R.A., Dumelin C.E., Keefe A.D. DNA-encoded chemistry: Enabling the deeper sampling of chemical space. Nat. Rev. Drug Discov. 2017;16:131–147. doi: 10.1038/nrd.2016.213. [PubMed] [CrossRef] [Google Scholar]

25. Chan A.I., McGregor L.M., Liu D.R. Novel selection methods for DNA-encoded chemical libraries. Curr. Opin. Chem. Biol. 2015;26:55–61. doi: 10.1016/j.cbpa.2015.02.010. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

26. Gerry C.J., Wawer M.J., Clemons P.A., Schreiber S.L. DNA Barcoding a Complete Matrix of Stereoisomeric Small Molecules. J. Am. Chem. Soc. 2019;141:10225–10235. doi: 10.1021/jacs.9b01203. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

27. Dahlin J.L., Nissink J.W.M., Strasser J.M., Francis S., Higgins L., Zhou H., Zhang Z., Walters M.A. PAINS in the Assay: Chemical Mechanisms of Assay Interference and Promiscuous Enzymatic Inhibition Observed during a Sulfhydryl-Scavenging HTS. J. Med. Chem. 2015;58:2091–2113. doi: 10.1021/jm5019093. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

28. Baell J., Walters M.A. Chemistry: Chemical con artists foil drug discovery. Nature. 2014;513:481–483. doi: 10.1038/513481a. [PubMed] [CrossRef] [Google Scholar]

29. Hughes J., Rees S., Kalindjian S., Philpott K. Principles of early drug discovery. Br. J. Pharmacol. 2011;162:1239–1249. doi: 10.1111/j.1476-5381.2010.01127.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

30. An W.F., Tolliday N. Cell-Based Assays for High-Throughput Screening. Mol. Biotechnol. 2010;45:180–186. doi: 10.1007/s12033-010-9251-z. [PubMed] [CrossRef] [Google Scholar]

31. Duggirala N.K., Perry M.L., Almarsson Ö., Zaworotko M.J. Pharmaceutical cocrystals: Along the path to improved medicines. Chem. Commun. 2016;52:640–655. doi: 10.1039/C5CC08216A. [PubMed] [CrossRef] [Google Scholar]

32. Congreve M., Murray C.W., Blundell T.L. Keynote review: Structural biology and drug discovery. Drug Discov. Today. 2005;10:895–907. doi: 10.1016/S1359-6446(05)03484-7. [PubMed] [CrossRef] [Google Scholar]

33. Evanthia L., George S., Demetrios K.V., Zoe C. Structure-Based Virtual Screening for Drug Discovery: Principles, Applications and Recent Advances. Curr. Top. Med. Chem. 2014;14:1923–1938. [PMC free article] [PubMed] [Google Scholar]

34. Verdonk M.L., Cole J.C., Hartshorn M.J., Murray C.W., Taylor R.D. Improved protein–ligand docking using GOLD. Proteins Struct. Funct. Bioinform. 2003;52:609–623. doi: 10.1002/prot.10465. [PubMed] [CrossRef] [Google Scholar]

35. Brunger A.T. X-ray crystallography and NMR reveal complementary views of structure and dynamics. Nat. Struct. Biol. 1997;4:862–865. [PubMed] [Google Scholar]

36. Cassiday L. Structural biology: More than a crystallographer. Nature. 2014;505:711–713. doi: 10.1038/nj7485-711a. [PubMed] [CrossRef] [Google Scholar]

37. Shi Y. A Glimpse of Structural Biology through X-Ray Crystallography. Cell. 2014;159:995–1014. doi: 10.1016/j.cell.2014.10.051. [PubMed] [CrossRef] [Google Scholar]

38. Wagner G. An account of NMR in structural biology. Nat. Struct. Biol. 1997;4:841–844. [PubMed] [Google Scholar]

39. Howard M.J. Protein NMR spectroscopy. Curr. Biol. 1998;8:R331–R333. doi: 10.1016/S0960-9822(98)70214-3. [PubMed] [CrossRef] [Google Scholar]

40. Nogales E. The development of cryo-EM into a mainstream structural biology technique. Nat. Methods. 2016;13:24–27. doi: 10.1038/nmeth.3694. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

41. Callaway E. The revolution will not be crystallized: A new method sweeps through structural biology. Nature. 2015;525:172–174. doi: 10.1038/525172a. [PubMed] [CrossRef] [Google Scholar]

42. Waterhouse A., Bertoni M., Bienert S., Studer G., Tauriello G., Gumienny R., Heer F.T., de Beer T.A.P., Rempfer C., Bordoli L., et al. SWISS-MODEL: Homology modelling of protein structures and complexes. Nucleic Acids Res. 2018;46:W296–W303. doi: 10.1093/nar/gky427. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

43. Rohl C.A., Strauss C.E.M., Misura K.M.S., Baker D. Methods in Enzymology. Volume 383. Academic Press; Cambridge, MA, USA: 2004. Protein Structure Prediction Using Rosetta; pp. 66–93. [PubMed] [Google Scholar]

44. Zheng H., Hou J., Zimmerman M.D., Wlodawer A., Minor W. The future of crystallography in drug discovery. Expert Opin. Drug Discov. 2014;9:125–137. doi: 10.1517/17460441.2014.872623. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

45. Pellecchia M., Sem D.S., Wuthrich K. NMR in drug discovery. Nat. Rev. Drug Discov. 2002;1:211–219. doi: 10.1038/nrd748. [PubMed] [CrossRef] [Google Scholar]

46. Fesik S.W., Zuiderweg E.R., Olejniczak E.T., Gampe R.T., Jr. NMR methods for determining the structures of enzyme/inhibitor complexes as an aid in drug design. Biochem. Pharmacol. 1990;40:161–167. doi: 10.1016/0006-2952(90)90191-M. [PubMed] [CrossRef] [Google Scholar]

47. Shuker S.B., Hajduk P.J., Meadows R.P., Fesik S.W. Discovering high-affinity ligands for proteins: SAR by NMR. Science. 1996;274:1531–1534. doi: 10.1126/science.274.5292.1531. [PubMed] [CrossRef] [Google Scholar]

48. Harner M.J., Frank A.O., Fesik S.W. Fragment-based drug discovery using NMR spectroscopy. J. Biomol. NMR. 2013;56:65–75. doi: 10.1007/s10858-013-9740-z. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

49. Matthies D., Bae C., Toombes G.E.S., Fox T., Bartesaghi A., Subramaniam S., Swartz K.J. Single-particle cryo-EM structure of a voltage-activated potassium channel in lipid nanodiscs. eLife. 2018;7:e37558. doi: 10.7554/eLife.37558. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

50. Ceska T., Chung C.-W., Cooke R., Phillips C., Williams P.A. Cryo-EM in drug discovery. Biochem. Soc. Trans. 2019;47:281–293. doi: 10.1042/BST20180267. [PubMed] [CrossRef] [Google Scholar]

51. Fauman E.B., Rai B.K., Huang E.S. Structure-based druggability assessment—Identifying suitable targets for small molecule therapeutics. Curr. Opin. Chem. Biol. 2011;15:463–468. doi: 10.1016/j.cbpa.2011.05.020. [PubMed] [CrossRef] [Google Scholar]

52. Unver M.Y., Gierse R.M., Ritchie H., Hirsch A.K.H. Druggability Assessment of Targets Used in Kinetic Target-Guided Synthesis. J. Med. Chem. 2018;61:9395–9409. doi: 10.1021/acs.jmedchem.8b00266. [PubMed] [CrossRef] [Google Scholar]

53. Thomas S.E., Collins P., James R.H., Mendes V., Charoensutthivarakul S., Radoux C., Abell C., Coyne A.G., Floto R.A., Delft F.v., et al. Structure-guided fragment-based drug discovery at the synchrotron: Screening binding sites and correlations with hotspot mapping. Philos. Trans. R. Soc. A Math. Phys. Eng. Sci. 2019;377:20180422. doi: 10.1098/rsta.2018.0422. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

54. Cheng A.C., Coleman R.G., Smyth K.T., Cao Q., Soulard P., Caffrey D.R., Salzberg A.C., Huang E.S. Structure-based maximal affinity model predicts small-molecule druggability. Nat. Biotechnol. 2007;25:71–75. doi: 10.1038/nbt1273. [PubMed] [CrossRef] [Google Scholar]

55. Alvarado C., Stahl E., Koessel K., Rivera A., Cherry B.R., Pulavarti S.V.S.R.K., Szyperski T., Cance W., Marlowe T. Development of a Fragment-Based Screening Assay for the Focal Adhesion Targeting Domain Using SPR and NMR. Molecules. 2019;24:3352. doi: 10.3390/molecules24183352. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

56. Nitsche C., Otting G. NMR studies of ligand binding. Curr. Opin. Struct. Biol. 2018;48:16–22. doi: 10.1016/j.sbi.2017.09.001. [PubMed] [CrossRef] [Google Scholar]

57. Norton R.S., Leung E.W., Chandrashekaran I.R., MacRaild C.A. Applications of (19)F-NMR in Fragment-Based Drug Discovery. Molecules. 2016;21:860. doi: 10.3390/molecules21070860. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

58. McKinney J.D., Richard A., Waller C., Newman M.C., Gerberick F. The Practice of Structure Activity Relationships (SAR) in Toxicology. Toxicol. Sci. 2000;56:8–17. doi: 10.1093/toxsci/56.1.8. [PubMed] [CrossRef] [Google Scholar]

59. Drwal M.N., Griffith R. Combination of ligand- and structure-based methods in virtual screening. Drug Discov. Today Technol. 2013;10:e395–e401. doi: 10.1016/j.ddtec.2013.02.002. [PubMed] [CrossRef] [Google Scholar]

60. Abagyan R., Totrov M. High-throughput docking for lead generation. Curr. Opin. Chem. Biol. 2001;5:375–382. doi: 10.1016/S1367-5931(00)00217-9. [PubMed] [CrossRef] [Google Scholar]

61. Macalino S.J.Y., Gosu V., Hong S., Choi S. Role of computer-aided drug design in modern drug discovery. Arch. Pharm. Res. 2015;38:1686–1701. doi: 10.1007/s12272-015-0640-5. [PubMed] [CrossRef] [Google Scholar]

62. Wang X., Song K., Li L., Chen L. Structure-Based Drug Design Strategies and Challenges. Curr. Top. Med. Chem. 2018;18:998–1006. doi: 10.2174/1568026618666180813152921. [PubMed] [CrossRef] [Google Scholar]

63. Batool M., Ahmad B., Choi S. A Structure-Based Drug Discovery Paradigm. Int. J. Mol. Sci. 2019;20:2783. doi: 10.3390/ijms20112783. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

64. Halder G., Johnson R.L. Hippo signaling: Growth control and beyond. Development. 2011;138:9–22. doi: 10.1242/dev.045500. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

65. Fu V., Plouffe S.W., Guan K.L. The Hippo pathway in organ development, homeostasis, and regeneration. Curr. Opin. Cell Biol. 2018;49:99–107. doi: 10.1016/j.ceb.2017.12.012. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

66. Yu F.X., Guan K.L. The Hippo pathway: Regulators and regulations. Genes Dev. 2013;27:355–371. doi: 10.1101/gad.210773.112. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

67. Santucci M., Vignudelli T., Ferrari S., Mor M., Scalvini L., Bolognesi M.L., Uliassi E., Costi M.P. The Hippo Pathway and YAP/TAZ–TEAD Protein–Protein Interaction as Targets for Regenerative Medicine and Cancer Treatment. J. Med. Chem. 2015;58:4857–4873. doi: 10.1021/jm501615v. [PubMed] [CrossRef] [Google Scholar]

68. Zanconato F., Cordenonsi M., Piccolo S. YAP/TAZ at the Roots of Cancer. Cancer Cell. 2016;29:783–803. doi: 10.1016/j.ccell.2016.05.005. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

69. Yin M., Zhang L. Hippo signaling: A hub of growth control, tumor suppression and pluripotency maintenance. J. Genet. Genom. 2011;38:471–481. doi: 10.1016/j.jgg.2011.09.009. [PubMed] [CrossRef] [Google Scholar]

70. Cairns L., Tran T., Kavran J.M. Structural Insights into the Regulation of Hippo Signaling. ACS Chem. Biol. 2017;12:601–610. doi: 10.1021/acschembio.6b01058. [PubMed] [CrossRef] [Google Scholar]

71. Li Z., Zhao B., Wang P., Chen F., Dong Z., Yang H., Guan K.L., Xu Y. Structural insights into the YAP and TEAD complex. Genes Dev. 2010;24:235–240. doi: 10.1101/gad.1865810. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

72. Pobbati A.V., Chan S.W., Lee I., Song H., Hong W. Structural and functional similarity between the Vgll1-TEAD and the YAP-TEAD complexes. Structure. 2012;20:1135–1140. doi: 10.1016/j.str.2012.04.004. [PubMed] [CrossRef] [Google Scholar]

73. Kaan H.Y.K., Chan S.W., Tan S.K.J., Guo F., Lim C.J., Hong W., Song H. Crystal structure of TAZ-TEAD complex reveals a distinct interaction mode from that of YAP-TEAD complex. Sci. Rep. 2017;7:2035. doi: 10.1038/s41598-017-02219-9. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

74. Pobbati A.V., Han X., Hung A.W., Weiguang S., Huda N., Chen G.Y., Kang C., Chia C.S., Luo X., Hong W., et al. Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy. Structure. 2015;23:2076–2086. doi: 10.1016/j.str.2015.09.009. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

75. Zhou Z., Hu T., Xu Z., Lin Z., Zhang Z., Feng T., Zhu L., Rong Y., Shen H., Luk J.M., et al. Targeting Hippo pathway by specific interruption of YAP-TEAD interaction using cyclic YAP-like peptides. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2015;29:724–732. doi: 10.1096/fj.14-262980. [PubMed] [CrossRef] [Google Scholar]

76. Zhang Z., Lin Z., Zhou Z., Shen H.C., Yan S.F., Mayweg A.V., Xu Z., Qin N., Wong J.C., Zhang Z., et al. Structure-Based Design and Synthesis of Potent Cyclic Peptides Inhibiting the YAP–TEAD Protein–Protein Interaction. ACS Med. Chem. Lett. 2014;5:993–998. doi: 10.1021/ml500160m. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

77. Jiao S., Wang H., Shi Z., Dong A., Zhang W., Song X., He F., Wang Y., Zhang Z., Wang W., et al. A Peptide Mimicking VGLL4 Function Acts as a YAP Antagonist Therapy against Gastric Cancer. Cancer Cell. 2014;25:166–180. doi: 10.1016/j.ccr.2014.01.010. [PubMed] [CrossRef] [Google Scholar]

78. Liu-Chittenden Y., Huang B., Shim J.S., Chen Q., Lee S.J., Anders R.A., Liu J.O., Pan D. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 2012;26:1300–1305. doi: 10.1101/gad.192856.112. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

79. Crook Z.R., Sevilla G.P., Friend D., Brusniak M.Y., Bandaranayake A.D., Clarke M., Gewe M., Mhyre A.J., Baker D., Strong R.K., et al. Mammalian display screening of diverse cystine-dense peptides for difficult to drug targets. Nat. Commun. 2017;8:2244. doi: 10.1038/s41467-017-02098-8. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

80. Noland C.L., Gierke S., Schnier P.D., Murray J., Sandoval W.N., Sagolla M., Dey A., Hannoush R.N., Fairbrother W.J., Cunningham C.N. Palmitoylation of TEAD Transcription Factors Is Required for Their Stability and Function in Hippo Pathway Signaling. Structure. 2016;24:179–186. doi: 10.1016/j.str.2015.11.005. [PubMed] [CrossRef] [Google Scholar]

81. Gibault F., Sturbaut M., Bailly F., Melnyk P., Cotelle P. Targeting Transcriptional Enhanced Associate Domains (TEADs) J. Med. Chem. 2018;61:5057–5072. doi: 10.1021/acs.jmedchem.7b00879. [PubMed] [CrossRef] [Google Scholar]

82. Kunig V.B.K., Potowski M., Akbarzadeh M., Klika Škopić M., Dos Santos Smith D., Arendt L., Dormuth I., Adihou H., Andlovic B., Karatas H., et al. TEAD-YAP interaction inhibitors and MDM2 binders from DNA-encoded indole-focused Ugi-peptidomimetics. Angew. Chem. Int. Ed. 2020 doi: 10.1002/anie.202006280. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

83. Chan P., Han X., Zheng B., DeRan M., Yu J., Jarugumilli G.K., Deng H., Pan D., Luo X., Wu X. Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway. Nat. Chem. Biol. 2016;12:282. doi: 10.1038/nchembio.2036. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

84. Holden J.K., Crawford J.J., Noland C.L., Schmidt S., Zbieg J.R., Lacap J.A., Zang R., Miller G.M., Zhang Y., Beroza P., et al. Small Molecule Dysregulation of TEAD Lipidation Induces a Dominant-Negative Inhibition of Hippo Pathway Signaling. Cell Rep. 2020;31:107809. doi: 10.1016/j.celrep.2020.107809. [PubMed] [CrossRef] [Google Scholar]

85. Rajan S., Jang Y., Kim C.-H., Kim W., Toh H.T., Jeon J., Song B., Serra A., Lescar J., Yoo J.Y., et al. PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function. Nat. Chem. Biol. 2020 doi: 10.1038/s41589-020-0553-6. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

86. Anantharajan J., Zhou H., Zhang L., Hotz T., Vincent M.Y., Blevins M.A., Jansson A.E., Kuan J.W.L., Ng E.Y., Yeo Y.K., et al. Structural and Functional Analyses of an Allosteric EYA2 Phosphatase Inhibitor That Has On-Target Effects in Human Lung Cancer Cells. Mol. Cancer Ther. 2019;18:1484–1496. doi: 10.1158/1535-7163.MCT-18-1239. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

87. Pearen M.A., Muscat G.E.O. Minireview: Nuclear Hormone Receptor 4A Signaling: Implications for Metabolic Disease. Mol. Endocrinol. 2010;24:1891–1903. doi: 10.1210/me.2010-0015. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

88. Decressac M., Volakakis N., Björklund A., Perlmann T. NURR1 in Parkinson disease—From pathogenesis to therapeutic potential. Nat. Rev. Neurol. 2013;9:629–636. doi: 10.1038/nrneurol.2013.209. [PubMed] [CrossRef] [Google Scholar]

89. Wang Z., Benoit G., Liu J., Prasad S., Aarnisalo P., Liu X., Xu H., Walker N.P.C., Perlmann T. Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature. 2003;423:555–560. doi: 10.1038/nature01645. [PubMed] [CrossRef] [Google Scholar]

90. De Vera I.M.S., Munoz-Tello P., Zheng J., Dharmarajan V., Marciano D.P., Matta-Camacho E., Giri P.K., Shang J., Hughes T.S., Rance M., et al. Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1. Structure. 2019;27:66–77. doi: 10.1016/j.str.2018.10.002. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

91. Windshügel B. Structural insights into ligand-binding pocket formation in Nurr1 by molecular dynamics simulations. J. Biomol. Struct. Dyn. 2019;37:4651–4657. doi: 10.1080/07391102.2018.1559099. [PubMed] [CrossRef] [Google Scholar]

92. Poulsen A., Kang C., Keller T.H. Drug design for flavivirus proteases: What are we missing? Curr. Pharm. Des. 2014;20:3422–3427. doi: 10.2174/13816128113199990633. [PubMed] [CrossRef] [Google Scholar]

93. Pierson T.C., Diamond M.S. Fields Virology. 6th ed. Lippincott Williams & Wilkins; Philadelphia, PA, USA: 2013. Flaviviruses; pp. 747–794. [Google Scholar]

94. Lindenbach B.D., Thiel H.J., Rice C.M. Fields Virology. 6th ed. Lippincott Williams & Wilkins; Philadelphia, PA, USA: 2013. Flaviviridae; pp. 712–746. [Google Scholar]

95. Weaver S.C., Costa F., Garcia-Blanco M.A., Ko A.I., Ribeiro G.S., Saade G., Shi P.Y., Vasilakis N. Zika virus: History, emergence, biology, and prospects for control. Antivir. Res. 2016;130:69–80. doi: 10.1016/j.antiviral.2016.03.010. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

96. Petersen L.R., Jamieson D.J., Powers A.M., Honein M.A. Zika Virus. N. Engl. J. Med. 2016;374:1552–1563. doi: 10.1056/NEJMra1602113. [PubMed] [CrossRef] [Google Scholar]

97. Broutet N., Krauer F., Riesen M., Khalakdina A., Almiron M., Aldighieri S., Espinal M., Low N., Dye C. Zika Virus as a Cause of Neurologic Disorders. N. Engl. J. Med. 2016;374:1506–1509. doi: 10.1056/NEJMp1602708. [PubMed] [CrossRef] [Google Scholar]

98. Carteaux G., Maquart M., Bedet A., Contou D., Brugieres P., Fourati S., Cleret de Langavant L., de Broucker T., Brun-Buisson C., Leparc-Goffart I., et al. Zika Virus Associated with Meningoencephalitis. N. Engl. J. Med. 2016;374:1595–1596. doi: 10.1056/NEJMc1602964. [PubMed] [CrossRef] [Google Scholar]

99. Mecharles S., Herrmann C., Poullain P., Tran T.H., Deschamps N., Mathon G., Landais A., Breurec S., Lannuzel A. Acute myelitis due to Zika virus infection. Lancet. 2016;387:1481. doi: 10.1016/S0140-6736(16)00644-9. [PubMed] [CrossRef] [Google Scholar]

100. Baronti C., Piorkowski G., Charrel R.N., Boubis L., Leparc-Goffart I., de Lamballerie X. Complete coding sequence of zika virus from a French polynesia outbreak in 2013. Genome Announc. 2014;2:e00500-14. doi: 10.1128/genomeA.00500-14. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

101. Clum S., Ebner K.E., Padmanabhan R. Cotranslational membrane insertion of the serine proteinase precursor NS2B-NS3(Pro) of dengue virus type 2 is required for efficient in vitro processing and is mediated through the hydrophobic regions of NS2B. J. Biol. Chem. 1997;272:30715–30723. doi: 10.1074/jbc.272.49.30715. [PubMed] [CrossRef] [Google Scholar]

102. Li Y., Li Q., Wong Y.L., Liew L.S., Kang C. Membrane topology of NS2B of dengue virus revealed by NMR spectroscopy. Biochim. Biophys. Acta. 2015;1848:2244–2252. doi: 10.1016/j.bbamem.2015.06.010. [PubMed] [CrossRef] [Google Scholar]

103. Brecher M., Zhang J., Li H. The flavivirus protease as a target for drug discovery. Virol. Sin. 2013;28:326–336. doi: 10.1007/s12250-013-3390-x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

104. Phoo W.W., Zhang Z., Wirawan M., Chew E.J.C., Chew A.B.L., Kouretova J., Steinmetzer T., Luo D. Structures of Zika virus NS2B-NS3 protease in complex with peptidomimetic inhibitors. Antivir. Res. 2018;160:17–24. doi: 10.1016/j.antiviral.2018.10.006. [PubMed] [CrossRef] [Google Scholar]

105. Shiryaev S.A., Farhy C., Pinto A., Huang C.-T., Simonetti N., Ngono A.E., Dewing A., Shresta S., Pinkerton A.B., Cieplak P., et al. Characterization of the Zika virus two-component NS2B-NS3 protease and structure-assisted identification of allosteric small-molecule antagonists. Antivir. Res. 2017;143:218–229. doi: 10.1016/j.antiviral.2017.04.015. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

106. Zhang Z., Li Y., Loh Y.R., Phoo W.W., Hung A.W., Kang C., Luo D. Crystal structure of unlinked NS2B-NS3 protease from Zika virus. Science. 2016;354:1597–1600. doi: 10.1126/science.aai9309. [PubMed] [CrossRef] [Google Scholar]

107. Tian H., Ji X., Yang X., Xie W., Yang K., Chen C., Wu C., Chi H., Mu Z., Wang Z., et al. The crystal structure of Zika virus helicase: Basis for antiviral drug design. Protein Cell. 2016 doi: 10.1007/s13238-016-0275-4. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

108. Phoo W.W., Li Y., Zhang Z., Lee M.Y., Loh Y.R., Tan Y.B., Ng E.Y., Lescar J., Kang C., Luo D. Structure of the NS2B-NS3 protease from Zika virus after self-cleavage. Nat. Commun. 2016;7:13410. doi: 10.1038/ncomms13410. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

109. Lei J., Hansen G., Nitsche C., Klein C.D., Zhang L., Hilgenfeld R. Crystal structure of Zika virus NS2B-NS3 protease in complex with a boronate inhibitor. Science. 2016;353:503–505. doi: 10.1126/science.aag2419. [PubMed] [CrossRef] [Google Scholar]

110. Nitsche C., Onagi H., Quek J.P., Otting G., Luo D., Huber T. Biocompatible Macrocyclization between Cysteine and 2-Cyanopyridine Generates Stable Peptide Inhibitors. Org. Lett. 2019;21:4709–4712. doi: 10.1021/acs.orglett.9b01545. [PubMed] [CrossRef] [Google Scholar]

111. Aleshin A.E., Shiryaev S.A., Strongin A.Y., Liddington R.C. Structural evidence for regulation and specificity of flaviviral proteases and evolution of the Flaviviridae fold. Protein. Sci. 2007;16:795–806. doi: 10.1110/ps.072753207. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

112. Chandramouli S., Joseph J.S., Daudenarde S., Gatchalian J., Cornillez-Ty C., Kuhn P. Serotype-specific structural differences in the protease-cofactor complexes of the dengue virus family. J. Virol. 2010;84:3059–3067. doi: 10.1128/JVI.02044-09. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

113. Robin G., Chappell K., Stoermer M.J., Hu S.H., Young P.R., Fairlie D.P., Martin J.L. Structure of West Nile virus NS3 protease: Ligand stabilization of the catalytic conformation. J. Mol. Biol. 2009;385:1568–1577. doi: 10.1016/j.jmb.2008.11.026. [PubMed] [CrossRef] [Google Scholar]

114. Hammamy M.Z., Haase C., Hammami M., Hilgenfeld R., Steinmetzer T. Development and characterization of new peptidomimetic inhibitors of the West Nile virus NS2B-NS3 protease. Chem. Med. Chem. 2013;8:231–241. doi: 10.1002/cmdc.201200497. [PubMed] [CrossRef] [Google Scholar]

115. Gruba N., Martinez J.I.R., Grzywa R., Wysocka M., Skorenski M., Dabrowska A., Lecka M., Suder P., Sienczyk M., Pyrc K., et al. One Step Beyond: Design of Substrates Spanning Primed Positions of Zika Virus NS2B-NS3 Protease. ACS Med. Chem. Lett. 2018;9:1025–1029. doi: 10.1021/acsmedchemlett.8b00316. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

116. Kang C., Gayen S., Wang W., Severin R., Chen A.S., Lim H.A., Chia C.S., Schuller A., Doan D.N., Poulsen A., et al. Exploring the binding of peptidic West Nile virus NS2B-NS3 protease inhibitors by NMR. Antivir. Res. 2013;97:137–144. doi: 10.1016/j.antiviral.2012.11.008. [PubMed] [CrossRef] [Google Scholar]

117. Li Q., Kang C. Insights into Structures and Dynamics of Flavivirus Proteases from NMR Studies. Int. J. Mol. Sci. 2020;21:2527. doi: 10.3390/ijms21072527. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

118. Li Y., Zhang Z., Phoo W.W., Loh Y.R., Wang W., Liu S., Chen M.W., Hung A.W., Keller T.H., Luo D., et al. Structural Dynamics of Zika Virus NS2B-NS3 Protease Binding to Dipeptide Inhibitors. Structure. 2017;25:1242–1250. doi: 10.1016/j.str.2017.06.006. [PubMed] [CrossRef] [Google Scholar]

119. Quek J.P., Liu S., Zhang Z., Li Y., Ng E.Y., Loh Y.R., Hung A.W., Luo D., Kang C. Identification and structural characterization of small molecule fragments targeting Zika virus NS2B-NS3 protease. Antivir. Res. 2020;175:104707. doi: 10.1016/j.antiviral.2020.104707. [PubMed] [CrossRef] [Google Scholar]

120. Lim S.P., Shi P.Y. West Nile virus drug discovery. Viruses. 2013;5:2977–3006. doi: 10.3390/v5122977. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

121. Lim S.P., Wang Q.Y., Noble C.G., Chen Y.L., Dong H., Zou B., Yokokawa F., Nilar S., Smith P., Beer D., et al. Ten years of dengue drug discovery: Progress and prospects. Antivir. Res. 2013;100:500–519. doi: 10.1016/j.antiviral.2013.09.013. [PubMed] [CrossRef] [Google Scholar]

122. Nitsche C., Behnam M.A., Steuer C., Klein C.D. Retro peptide-hybrids as selective inhibitors of the Dengue virus NS2B-NS3 protease. Antivir. Res. 2012;94:72–79. doi: 10.1016/j.antiviral.2012.02.008. [PubMed] [CrossRef] [Google Scholar]

123. Yin Z., Patel S.J., Wang W.L., Wang G., Chan W.L., Rao K.R., Alam J., Jeyaraj D.A., Ngew X., Patel V., et al. Peptide inhibitors of Dengue virus NS3 protease. Part 1: Warhead. Bioorg. Med. Chem. Lett. 2006;16:36–39. doi: 10.1016/j.bmcl.2005.09.062. [PubMed] [CrossRef] [Google Scholar]

124. Deng J., Li N., Liu H., Zuo Z., Liew O.W., Xu W., Chen G., Tong X., Tang W., Zhu J., et al. Discovery of novel small molecule inhibitors of dengue viral NS2B-NS3 protease using virtual screening and scaffold hopping. J. Med. Chem. 2012;55:6278–6293. doi: 10.1021/jm300146f. [PubMed] [CrossRef] [Google Scholar]

125. Yang C.C., Hsieh Y.C., Lee S.J., Wu S.H., Liao C.L., Tsao C.H., Chao Y.S., Chern J.H., Wu C.P., Yueh A. Novel dengue virus-specific NS2B/NS3 protease inhibitor, BP2109, discovered by a high-throughput screening assay. Antimicrob. Agents Chemother. 2011;55:229–238. doi: 10.1128/AAC.00855-10. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

126. Johnston P.A., Phillips J., Shun T.Y., Shinde S., Lazo J.S., Huryn D.M., Myers M.C., Ratnikov B.I., Smith J.W., Su Y., et al. HTS identifies novel and specific uncompetitive inhibitors of the two-component NS2B-NS3 proteinase of West Nile virus. Assay Drug Dev. Technol. 2007;5:737–750. doi: 10.1089/adt.2007.101. [PubMed] [CrossRef] [Google Scholar]

127. Sidique S., Shiryaev S.A., Ratnikov B.I., Herath A., Su Y., Strongin A.Y., Cosford N.D. Structure-activity relationship and improved hydrolytic stability of pyrazole derivatives that are allosteric inhibitors of West Nile Virus NS2B-NS3 proteinase. Bioorg. Med. Chem. Lett. 2009;19:5773–5777. doi: 10.1016/j.bmcl.2009.07.150. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

128. Koh-Stenta X., Joy J., Wang S.F., Kwek P.Z., Wee J.L., Wan K.F., Gayen S., Chen A.S., Kang C., Lee M.A., et al. Identification of covalent active site inhibitors of dengue virus protease. Drug Des. Devel. Ther. 2015;9:6389–6399. doi: 10.2147/DDDT.S94207. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

129. Li Y., Zhang Z., Phoo W.W., Loh Y.R., Li R., Yang H.Y., Jansson A.E., Hill J., Keller T.H., Nacro K., et al. Structural Insights into the Inhibition of Zika Virus NS2B-NS3 Protease by a Small-Molecule Inhibitor. Structure. 2018;26:555–564. doi: 10.1016/j.str.2018.02.005. [PubMed] [CrossRef] [Google Scholar]

130. Schöne T., Grimm L.L., Sakai N., Zhang L., Hilgenfeld R., Peters T. STD-NMR experiments identify a structural motif with novel second-site activity against West Nile virus NS2B-NS3 protease. Antivir. Res. 2017;146:174–183. doi: 10.1016/j.antiviral.2017.09.008. [PubMed] [CrossRef] [Google Scholar]

131. Kim Y.M., Gayen S., Kang C., Joy J., Huang Q., Chen A.S., Wee J.L., Ang M.J., Lim H.A., Hung A.W., et al. NMR analysis of a novel enzymatically active unlinked dengue NS2B-NS3 protease complex. J. Biol. Chem. 2013;288:12891–12900. doi: 10.1074/jbc.M112.442723. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

132. Su X.C., Ozawa K., Qi R., Vasudevan S.G., Lim S.P., Otting G. NMR analysis of the dynamic exchange of the NS2B cofactor between open and closed conformations of the West Nile virus NS2B-NS3 protease. PLoS Negl. Trop. Dis. 2009;3:e561. doi: 10.1371/journal.pntd.0000561. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

133. Nitsche C., Passioura T., Varava P., Mahawaththa M.C., Leuthold M.M., Klein C.D., Suga H., Otting G. De Novo Discovery of Nonstandard Macrocyclic Peptides as Noncompetitive Inhibitors of the Zika Virus NS2B-NS3 Protease. ACS Med. Chem. Lett. 2019;10:168–174. doi: 10.1021/acsmedchemlett.8b00535. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

134. Yao Y., Huo T., Lin Y.-L., Nie S., Wu F., Hua Y., Wu J., Kneubehl A.R., Vogt M.B., Rico-Hesse R., et al. Discovery, X-ray Crystallography and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B-NS3 Protease. J. Am. Chem. Soc. 2019;141:6832–6836. doi: 10.1021/jacs.9b02505. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

135. Yildiz M., Ghosh S., Bell J.A., Sherman W., Hardy J.A. Allosteric Inhibition of the NS2B-NS3 Protease from Dengue Virus. ACS Chem. Biol. 2013;8:2744–2752. doi: 10.1021/cb400612h. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

136. Othman R., Kiat T.S., Khalid N., Yusof R., Newhouse E.I., Newhouse J.S., Alam M., Rahman N.A. Docking of noncompetitive inhibitors into dengue virus type 2 protease: Understanding the interactions with allosteric binding sites. J. Chem. Inf. Model. 2008;48:1582–1591. doi: 10.1021/ci700388k. [PubMed] [CrossRef] [Google Scholar]

137. Ekonomiuk D., Su X.C., Ozawa K., Bodenreider C., Lim S.P., Otting G., Huang D., Caflisch A. Flaviviral protease inhibitors identified by fragment-based library docking into a structure generated by molecular dynamics. J. Med. Chem. 2009;52:4860–4868. doi: 10.1021/jm900448m. [PubMed] [CrossRef] [Google Scholar]

138. Ekonomiuk D., Su X.C., Ozawa K., Bodenreider C., Lim S.P., Yin Z., Keller T.H., Beer D., Patel V., Otting G., et al. Discovery of a non-peptidic inhibitor of west nile virus NS3 protease by high-throughput docking. PLoS Negl. Trop. Dis. 2009;3:e356. doi: 10.1371/journal.pntd.0000356. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

139. Knox J.E., Ma N.L., Yin Z., Patel S.J., Wang W.L., Chan W.L., Rao K.R.R., Wang G., Ngew X., Patel V., et al. Peptide inhibitors of West Nile NS3 protease: SAR study of tetrapeptide aldehyde inhibitors. J. Med. Chem. 2006;49:6585–6590. doi: 10.1021/jm0607606. [PubMed] [CrossRef] [Google Scholar]

140. Zhou H., Zhang L., Vartuli R.L., Ford H.L., Zhao R. The Eya phosphatase: Its unique role in cancer. Int. J. Biochem. Cell Biol. 2018;96:165–170. doi: 10.1016/j.biocel.2017.09.001. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

141. Patrick A.N., Cabrera J.H., Smith A.L., Chen X.S., Ford H.L., Zhao R. Structure-function analyses of the human SIX1–EYA2 complex reveal insights into metastasis and BOR syndrome. Nat. Struct. Mol. Biol. 2013;20:447–453. doi: 10.1038/nsmb.2505. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

142. Kumar J.P. The sine oculis homeobox (SIX) family of transcription factors as regulators of development and disease. Cell. Mol. Life Sci. 2009;66:565–583. doi: 10.1007/s00018-008-8335-4. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

143. Zhou H., Blevins M.A., Hsu J.Y., Kong D., Galbraith M.D., Goodspeed A., Culp-Hill R., Oliphant M.U.J., Ramirez D., Zhang L., et al. Identification of a Small-Molecule Inhibitor That Disrupts the SIX1/EYA2 Complex, EMT, and Metastasis. Cancer Res. 2020;80:2689–2702. doi: 10.1158/0008-5472.CAN-20-0435. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

144. Christensen K.L., Patrick A.N., McCoy E.L., Ford H.L. The six family of homeobox genes in development and cancer. Adv. Cancer Res. 2008;101:93–126. [PubMed] [Google Scholar]

145. Blevins M.A., Towers C.G., Patrick A.N., Zhao R., Ford H.L. The SIX1-EYA transcriptional complex as a therapeutic target in cancer. Exp. Opin. Ther. Targets. 2015;19:213–225. doi: 10.1517/14728222.2014.978860. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

146. Rebay I. Multiple Functions of the Eya Phosphotyrosine Phosphatase. Mol. Cell. Biol. 2016;36:668–677. doi: 10.1128/MCB.00976-15. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

147. Li X., Oghi K.A., Zhang J., Krones A., Bush K.T., Glass C.K., Nigam S.K., Aggarwal A.K., Maas R., Rose D.W., et al. Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature. 2003;426:247–254. doi: 10.1038/nature02083. [PubMed] [CrossRef] [Google Scholar]

148. Rayapureddi J.P., Kattamuri C., Steinmetz B.D., Frankfort B.J., Ostrin E.J., Mardon G., Hegde R.S. Eyes absent represents a class of protein tyrosine phosphatases. Nature. 2003;426:295–298. doi: 10.1038/nature02093. [PubMed] [CrossRef] [Google Scholar]

149. Tootle T.L., Silver S.J., Davies E.L., Newman V., Latek R.R., Mills I.A., Selengut J.D., Parlikar B.E., Rebay I. The transcription factor Eyes absent is a protein tyrosine phosphatase. Nature. 2003;426:299–302. doi: 10.1038/nature02097. [PubMed] [CrossRef] [Google Scholar]

150. Pandey R.N., Rani R., Yeo E.J., Spencer M., Hu S., Lang R.A., Hegde R.S. The Eyes Absent phosphatase-transactivator proteins promote proliferation, transformation, migration, and invasion of tumor cells. Oncogene. 2010;29:3715–3722. doi: 10.1038/onc.2010.122. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

151. Tonks N.K. Protein tyrosine phosphatases: From genes, to function, to disease. Nat. Rev. Mol. Cell Biol. 2006;7:833–846. doi: 10.1038/nrm2039. [PubMed] [CrossRef] [Google Scholar]

152. Jung S.K., Jeong D.G., Chung S.J., Kim J.H., Park B.C., Tonks N.K., Ryu S.E., Kim S.J. Crystal structure of ED-Eya2: Insight into dual roles as a protein tyrosine phosphatase and a transcription factor. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2010;24:560–569. doi: 10.1096/fj.09-143891. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

153. Cook P.J., Ju B.G., Telese F., Wang X., Glass C.K., Rosenfeld M.G. Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. Nature. 2009;458:591–596. doi: 10.1038/nature07849. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

154. Krishnan N., Jeong D.G., Jung S.K., Ryu S.E., Xiao A., Allis C.D., Kim S.J., Tonks N.K. Dephosphorylation of the C-terminal tyrosyl residue of the DNA damage-related histone H2A.X is mediated by the protein phosphatase eyes absent. J. Biol. Chem. 2009;284:16066–16070. doi: 10.1074/jbc.C900032200. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

155. Liu Y., Long Y.H., Wang S.Q., Li Y.F., Zhang J.H. Phosphorylation of H2A.X(T)(yr39) positively regulates DNA damage response and is linked to cancer progression. FEBS J. 2016;283:4462–4473. doi: 10.1111/febs.13951. [PubMed] [CrossRef] [Google Scholar]

156. Yuan B., Cheng L., Chiang H.C., Xu X., Han Y., Su H., Wang L., Zhang B., Lin J., Li X., et al. A phosphotyrosine switch determines the antitumor activity of ERbeta. J. Clin. Investig. 2014;124:3378–3390. doi: 10.1172/JCI74085. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

157. Mentel M., Ionescu A.E., Puscalau-Girtu I., Helm M.S., Badea R.A., Rizzoli S.O., Szedlacsek S.E. WDR1 is a novel EYA3 substrate and its dephosphorylation induces modifications of the cellular actin cytoskeleton. Sci. Rep. 2018;8:2910. doi: 10.1038/s41598-018-21155-w. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

158. Krueger A.B., Drasin D.J., Lea W.A., Patrick A.N., Patnaik S., Backos D.S., Matheson C.J., Hu X., Barnaeva E., Holliday M.J., et al. Allosteric inhibitors of the Eya2 phosphatase are selective and inhibit Eya2-mediated cell migration. J. Biol. Chem. 2014;289:16349–16361. doi: 10.1074/jbc.M114.566729. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

159. Krueger A.B., Dehdashti S.J., Southall N., Marugan J.J., Ferrer M., Li X., Ford H.L., Zheng W., Zhao R. Identification of a selective small-molecule inhibitor series targeting the eyes absent 2 (Eya2) phosphatase activity. J. Biomol. Screen. 2013;18:85–96. doi: 10.1177/1087057112453936. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

160. Rudmann D.G. On-target and off-target-based toxicologic effects. Toxicol. Pathol. 2013;41:310–314. doi: 10.1177/0192623312464311. [PubMed] [CrossRef] [Google Scholar]

161. Shraga A., Olshvang E., Davidzohn N., Khoshkenar P., Germain N., Shurrush K., Carvalho S., Avram L., Albeck S., Unger T., et al. Covalent Docking Identifies a Potent and Selective MKK7 Inhibitor. Cell Chem. Biol. 2019;26:98–108. doi: 10.1016/j.chembiol.2018.10.011. [PubMed] [CrossRef] [Google Scholar]

162. Chang R.L., Xie L., Xie L., Bourne P.E., Palsson B.Ø. Drug Off-Target Effects Predicted Using Structural Analysis in the Context of a Metabolic Network Model. PLoS Comput. Biol. 2010;6:e1000938. doi: 10.1371/journal.pcbi.1000938. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

163. Xie L., Xie L., Bourne P.E. Structure-based systems biology for analyzing off-target binding. Curr. Opin. Struct. Biol. 2011;21:189–199. doi: 10.1016/j.sbi.2011.01.004. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

164. Moumbock A.F.A., Li J., Mishra P., Gao M., Günther S. Current computational methods for predicting protein interactions of natural products. Comput. Struct. Biotechnol. J. 2019;17:1367–1376. doi: 10.1016/j.csbj.2019.08.008. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Page 2

Obtaining molecules to affect the function of a protein. Both phenotypic screening and target-based drug design can be utilized to develop small-molecule compounds.

Click on the image to see a larger version.