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RESEARCH ARTICLE
Contents Vol 71(12)

Imaginative Order from Reasonable Chaos: Conformation-Driven Activity and Reactivity in Exploring Protein–Ligand Interactions

Alexander F. Moore A , David J. Newman A B , Shoba Ranganathan A and Fei Liu A C
+ Author Affiliations
- Author Affiliations

A Department of Molecular Sciences, Macquarie University, North Ryde, NSW 2109, Australia.

B Newman Consulting LLC, Wayne, PA 19087, USA.

C Corresponding author. Email: fei.liu@mq.edu.au

Australian Journal of Chemistry 71(12) 917-930 https://doi.org/10.1071/CH18416
Submitted: 20 August 2018  Accepted: 9 October 2018   Published: 12 November 2018

Abstract

Sir Derek Barton’s seminal work on steroid conformational analysis opened up a new era of enquiry into how the preferred conformation of any molecule could have profound effects on its physical–chemical properties and activities. Conformation-based effects on molecular activity and reactivity continue to manifest, with one key area of investigation currently focussed on conformational entropy in driving protein–ligand interactions. Carrying on from Barton’s initial insight on natural product conformational properties, new questions now address how conformational flexibility within a bioactive natural product structural framework (reasonable chaos), can be directed to confer dynamically new protein–ligand interactions beyond the basic lock–key model (imaginative order). Here we summarise our work on exploring conformational diversity from fluorinated natural product fragments, and how this approach of conformation-coupled diversity-oriented synthesis can be used to iteratively derive ligands with enhanced specificity against highly homologous protein domains. Our results demonstrate that the conformation entropic states of highly conserved protein domains differ significantly, and this conformational diversity, beyond primary sequence analysis, can be duly captured and exploited by natural-product derived ligands with complementary conformational dynamics for enhancing recognition specificity in drug lead discovery.


References

[1]  D. H. R. Barton, Experientia 1950, 6, 316.
         | Crossref | GoogleScholarGoogle Scholar |

[2]  O. Bastiansen, O. Hassel, Nature 1946, 157, 765.
         | Crossref | GoogleScholarGoogle Scholar |

[3]  D. H. R. Barton, J. Chem. Soc. 1948, 340.
         | Crossref | GoogleScholarGoogle Scholar |

[4]  D. H. R. Barton, G. A. Schmeidler, J. Chem. Soc. 1948, 1197.
         | Crossref | GoogleScholarGoogle Scholar |

[5]  D. H. R. Barton, Science 1970, 169, 539.
         | Crossref | GoogleScholarGoogle Scholar |

[6]  D. H. R. Barton, E. Miller, J. Am. Chem. Soc. 1950, 72, 1066.
         | Crossref | GoogleScholarGoogle Scholar |

[7]  G. H. Alt, D. H. R. Barton, J. Chem. Soc. 1954, 4284.
         | Crossref | GoogleScholarGoogle Scholar |

[8]  D. H. R. Barton, N. J. Holness, J. Chem. Soc. 1952, 78.
         | Crossref | GoogleScholarGoogle Scholar |

[9]  A. M. Abel el Rehim, C. H. Carlisle, Chem. Ind. 1954, 279.

[10]  C. S. Barnes, D. H. R. Barton, J. S. Fawcett, B. R. Thomas, J. Chem. Soc. 1953, 576.
         | Crossref | GoogleScholarGoogle Scholar |

[11]  D. H. R. Barton, J. E. Page, E. W. Warnhoff, J. Chem. Soc. 1954, 2715.
         | Crossref | GoogleScholarGoogle Scholar |

[12]  D. H. R. Barton, D. A. Lewis, J. F. McGhie, J. Chem. Soc. 1957, 2907.
         | Crossref | GoogleScholarGoogle Scholar |

[13]  K. C. Nicolaou, D. Vourloumis, N. Winssinger, P. S. Baran, Angew. Chem. Int. Ed. 2000, 39, 44.
         | Crossref | GoogleScholarGoogle Scholar |

[14]  L. E. Zimmer, C. Sparr, R. Gilmour, Angew. Chem. Int. Ed. 2011, 50, 11860.
         | Crossref | GoogleScholarGoogle Scholar |

[15]  D. O’Hagan, Chem. Soc. Rev. 2008, 37, 308.
         | Crossref | GoogleScholarGoogle Scholar |

[16]  L. Hunter, Beilstein J. Org. Chem. 2010, 6, 38.
         | Crossref | GoogleScholarGoogle Scholar |

[17]  E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly, N. A. Meanwell, J. Med. Chem. 2015, 58, 8315.
         | Crossref | GoogleScholarGoogle Scholar |

[18]  G. G. Hammes, Y.-C. Chang, T. G. Oas, Proc. Natl. Acad. Sci. USA 2009, 106, 13737.
         | Crossref | GoogleScholarGoogle Scholar |

[19]  S.-R. Tzeng, C. G. Kalodimos, Nature 2012, 488, 236.
         | Crossref | GoogleScholarGoogle Scholar |

[20]  A. J. Wand, Curr. Opin. Struct. Biol. 2013, 23, 75.
         | Crossref | GoogleScholarGoogle Scholar |

[21]  D. L. Mobley, K. A. Dill, Structure 2009, 17, 489.
         | Crossref | GoogleScholarGoogle Scholar |

[22]  A. J. Wand, Nat. Struct. Biol. 2001, 8, 926.
         | Crossref | GoogleScholarGoogle Scholar |

[23]  T. I. Igumenova, K. K. Frederick, A. J. Wand, Chem. Rev. 2006, 106, 1672.
         | Crossref | GoogleScholarGoogle Scholar |

[24]  A. J. Baldwin, L. E. Kay, Nat. Chem. Biol. 2009, 5, 808.
         | Crossref | GoogleScholarGoogle Scholar |

[25]  D. D. Boehr, R. Nussinov, P. E. Wright, Nat. Chem. Biol. 2009, 5, 789.
         | Crossref | GoogleScholarGoogle Scholar |

[26]  K. Henzler-Wildman, D. Kern, Nature 2007, 450, 964.
         | Crossref | GoogleScholarGoogle Scholar |

[27]  A. Sekhar, L. E. Kay, Proc. Natl. Acad. Sci. USA 2013, 110, 12867.
         | Crossref | GoogleScholarGoogle Scholar |

[28]  H. N. Motlagh, J. O. Wrabl, J. Li, V. J. Hilser, Nature 2014, 508, 331.
         | Crossref | GoogleScholarGoogle Scholar |

[29]  Z. Li, S. Raychaudhuri, A. J. Wand, Protein Sci. 1996, 5, 2647.
         | Crossref | GoogleScholarGoogle Scholar |

[30]  D. Yang, L. E. Kay, J. Mol. Biol. 1996, 263, 369.
         | Crossref | GoogleScholarGoogle Scholar |

[31]  A. L. Lee, S. A. Kinnear, A. J. Wand, Nat. Struct. Mol. Biol. 2000, 7, 72.
         | Crossref | GoogleScholarGoogle Scholar |

[32]  A. Palmer, C. D. Kroenke, J. P. Loria, Methods Enzymol. 2001, 339, 204.
         | Crossref | GoogleScholarGoogle Scholar |

[33]  V. A. Jarymowycz, M. J. Stone, Chem. Rev. 2006, 106, 1624.
         | Crossref | GoogleScholarGoogle Scholar |

[34]  K. K. Frederick, M. S. Marlow, K. G. Valentine, A. J. Wand, Nature 2007, 448, 325.
         | Crossref | GoogleScholarGoogle Scholar |

[35]  M. S. Marlow, J. Dogan, K. K. Frederick, K. G. Valentine, A. J. Wand, Nat. Chem. Biol. 2010, 6, 352.
         | Crossref | GoogleScholarGoogle Scholar |

[36]  N. Popovych, S. Sun, R. H. Ebright, C. G. Kalodimos, Nat. Struct. Mol. Biol. 2006, 13, 831.
         | Crossref | GoogleScholarGoogle Scholar |

[37]  S.-R. Tzeng, C. G. Kalodimos, Nature 2009, 462, 368.
         | Crossref | GoogleScholarGoogle Scholar |

[38]  G. G. Romero, in Biased Signaling in Physiology, Pharmacology and Therapeutics (Ed. B. Arey) 2014, pp. 41–80 (Academic Press: San Diego, CA).

[39]  C. M. Petit, J. Zhang, P. J. Sapienza, E. J. Fuentes, A. L. Lee, Proc. Natl. Acad. Sci. USA 2009, 106, 18249.
         | Crossref | GoogleScholarGoogle Scholar |

[40]  S. Lu, S. Li, J. Zhang, Med. Res. Rev. 2014, 34, 1242.
         | Crossref | GoogleScholarGoogle Scholar |

[41]  Z. Huang, L. Mou, Q. Shen, S. Lu, C. Li, X. Liu, G. Wang, S. Li, L. Geng, Y. Liu, J. Wu, G. Chen, J. Zhang, Nucleic Acids Res. 2014, 42, D510.
         | Crossref | GoogleScholarGoogle Scholar |

[42]  D. Fabbro, S. W. Cowan-Jacob, H. Moebitz, Br. J. Pharmacol. 2015, 172, 2675.
         | Crossref | GoogleScholarGoogle Scholar |

[43]  R. S. K. Vijayan, P. He, V. Modi, K. C. Duong-Ly, H. Ma, J. R. Peterson, R. L. Dunbrack, R. M. Levy, J. Med. Chem. 2015, 58, 466.
         | Crossref | GoogleScholarGoogle Scholar |

[44]  M. Rask-Andersen, J. Zhang, D. Fabbro, H. B. Schiöth, Trends Pharmacol. Sci. 2014, 35, 604.
         | Crossref | GoogleScholarGoogle Scholar |

[45]  P. Cohen, FEBS J. 2001, 268, 5001.

[46]  G. P. Lisi, J. P. Loria, Chem. Rev. 2016, 116, 6323.
         | Crossref | GoogleScholarGoogle Scholar |

[47]  P. Cohen, Curr. Opin. Chem. Biol. 1999, 3, 459.
         | Crossref | GoogleScholarGoogle Scholar |

[48]  P. Cohen, Nat. Rev. Drug Discov. 2002, 1, 309.
         | Crossref | GoogleScholarGoogle Scholar |

[49]  D. Mochly-Rosen, K. Das, K. V. Grimes, Nat. Rev. Drug Discov. 2012, 11, 937.
         | Crossref | GoogleScholarGoogle Scholar |

[50]  P. Kulanthaivel, Y. F. Hallock, C. Boros, S. M. Hamilton, W. P. Janzen, L. M. Ballas, C. R. Loomis, J. B. Jiang, B. Katz, J. Am. Chem. Soc. 1993, 115, 6452.
         | Crossref | GoogleScholarGoogle Scholar |

[51]  P. Akamine, L. L. Brunton, H. D. Ou, J. M. Canaves, N.-h. Xuong, S. S. Taylor, Biochemistry 2004, 43, 85.
         | Crossref | GoogleScholarGoogle Scholar |

[52]  D. A. Walsh, S. M. V. Patten, FASEB J. 1994, 8, 1227.
         | Crossref | GoogleScholarGoogle Scholar |

[53]  J. Zheng, D. R. Knighton, L. F. Ten Eyck, R. Karlsson, N. Xuong, S. S. Taylor, J. M. Sowadski, Biochemistry 1993, 32, 2154.
         | Crossref | GoogleScholarGoogle Scholar |

[54]  D. A. Johnson, P. Akamine, E. Radzio-Andzelm, S. S. Taylor, Chem. Rev. 2001, 101, 2243.
         | Crossref | GoogleScholarGoogle Scholar |

[55]  S. S. Taylor, J. Yang, J. Wu, N. M. Haste, E. Radzio-Andzelm, G. Anand, Biochim. Biophys. Acta. Proteins Proteomics 2004, 1697, 259.
         | Crossref | GoogleScholarGoogle Scholar |

[56]  A. P. Kornev, S. S. Taylor, L. F. Ten Eyck, Proc. Natl. Acad. Sci. USA 2008, 105, 14377.
         | Crossref | GoogleScholarGoogle Scholar |

[57]  C. Hyeon, P. A. Jennings, J. A. Adams, J. N. Onuchic, Proc. Natl. Acad. Sci. USA 2009, 106, 3023.
         | Crossref | GoogleScholarGoogle Scholar |

[58]  J. Yang, E. J. Kennedy, J. Wu, M. S. Deal, J. Pennypacker, G. Ghosh, S. S. Taylor, J. Biol. Chem. 2009, 284, 6241.
         | Crossref | GoogleScholarGoogle Scholar |

[59]  A. P. Kornev, S. S. Taylor, Biochim. Biophys. Acta. Proteins Proteomics 2010, 1804, 440.
         | Crossref | GoogleScholarGoogle Scholar |

[60]  L. R. Masterson, C. Cheng, T. Yu, M. Tonelli, A. Kornev, S. S. Taylor, G. Veglia, Nat. Chem. Biol. 2010, 6, 821.
         | Crossref | GoogleScholarGoogle Scholar |

[61]  S. S. Taylor, A. P. Kornev, Trends Biochem. Sci. 2011, 36, 65.
         | Crossref | GoogleScholarGoogle Scholar |

[62]  A. K. Srivastava, L. R. McDonald, A. Cembran, J. Kim, L. R. Masterson, C. L. McClendon, S. S. Taylor, G. Veglia, Structure 2014, 22, 1735.
         | Crossref | GoogleScholarGoogle Scholar |

[63]  L. R. Masterson, A. Cembran, L. Shi, G. Veglia, in Advances in Protein Chemistry and Structural Biology (Eds C. Christov, T. Karabencheva-Christova) 2012, Vol. 87, pp. 363–389 (Academic Press: San Diego, CA).

[64]  G. Veglia, A. Cembran, FEBS J. 2013, 280, 5608.
         | Crossref | GoogleScholarGoogle Scholar |

[65]  L. G. Ahuja, A. P. Kornev, C. L. McClendon, G. Veglia, S. S. Taylor, Proc. Natl. Acad. Sci. USA 2017, 114, E931.
         | Crossref | GoogleScholarGoogle Scholar |

[66]  A. A. Polyansky, R. Zubac, B. Zagrovic, Methods Mol. Biol. 2012, 819, 327.
         | Crossref | GoogleScholarGoogle Scholar |

[67]  It is acknowledged that kinase Kd values are frequently inaccurate due to the restricted levels of ATP with a concentration less (≤1 mM) than that of a cell (1–5 mM) during experimental measurements. The complexity of these measurements, however, is not within the scope of this review. For more information please refer to: Anal. Biochem. 2017, 531, 67.

[68]  M. Fischer, R. G. Coleman, J. S. Fraser, B. K. Shoichet, Nat. Chem. 2014, 6, 575.
         | Crossref | GoogleScholarGoogle Scholar |

[69]  J. Mortier, C. Rakers, M. Bermudez, M. S. Murgueitio, S. Riniker, G. Wolber, Drug Discov. Today 2015, 20, 686.
         | Crossref | GoogleScholarGoogle Scholar |

[70]  B. Webb, A. Sali, Curr. Protoc. Protein Sci. 2016, 86, 2.9.1.
         | Crossref | GoogleScholarGoogle Scholar |

[71]  L.-G. Milroy, T. N. Grossmann, S. Hennig, L. Brunsveld, C. Ottmann, Chem. Rev. 2014, 114, 4695.
         | Crossref | GoogleScholarGoogle Scholar |

[72]  D. J. Newman, G. M. Cragg, J. Nat. Prod. 2016, 79, 629.
         | Crossref | GoogleScholarGoogle Scholar |

[73]  W. C. Tse, D. L. Boger, Chem. Biol. 2004, 11, 1607.
         | Crossref | GoogleScholarGoogle Scholar |

[74]  F. Aboul-ela, Future Med. Chem. 2010, 2, 93.
         | Crossref | GoogleScholarGoogle Scholar |

[75]  E. R. Lee, K. F. Blount, R. R. Breaker, RNA Biol. 2009, 6, 187.
         | Crossref | GoogleScholarGoogle Scholar |

[76]  E. M. Larsen, M. R. Wilson, R. E. Taylor, Nat. Prod. Rep. 2015, 32, 1183.
         | Crossref | GoogleScholarGoogle Scholar |

[77]  C. A. Lipinski, Adv. Drug Deliv. Rev. 2016, 101, 34.
         | Crossref | GoogleScholarGoogle Scholar |

[78]  M. Fouche, M. Schäfer, J. Berghausen, S. Desrayaud, M. Blatter, P. Piéchon, I. Dix, A. Martin Garcia, H. J. Roth, ChemMedChem 2016, 11, 1048.
         | Crossref | GoogleScholarGoogle Scholar |

[79]  P. Matsson, B. C. Doak, B. Over, J. Kihlberg, Adv. Drug Deliv. Rev. 2016, 101, 42.
         | Crossref | GoogleScholarGoogle Scholar |

[80]  M. R. Naylor, A. T. Bockus, M.-J. Blanco, R. S. Lokey, Curr. Opin. Chem. Biol. 2017, 38, 141.
         | Crossref | GoogleScholarGoogle Scholar |

[81]  D. J. Newman, Expert Opin. Drug Discov. 2018, 13, 379.
         | Crossref | GoogleScholarGoogle Scholar |

[82]  H. Qu, B. J. Smithies, T. Durek, D. J. Craik, Aust. J. Chem. 2017, 70, 152.
         | Crossref | GoogleScholarGoogle Scholar |

[83]  E. Valeur, S. M. Guéret, H. Adihou, R. Gopalakrishnan, M. Lemurell, H. Waldmann, T. N. Grossmann, A. T. Plowright, Angew. Chem. Int. Ed. 2017, 56, 10294.
         | Crossref | GoogleScholarGoogle Scholar |

[84]  C. P. Sommerhoff, O. Avrutina, H.-U. Schmoldt, D. Gabrijelcic-Geiger, U. Diederichsen, H. Kolmar, J. Mol. Biol. 2010, 395, 167.
         | Crossref | GoogleScholarGoogle Scholar |

[85]  A. Henninot, J. C. Collins, J. M. Nuss, J. Med. Chem. 2018, 61, 1382.
         | Crossref | GoogleScholarGoogle Scholar |

[86]  M. Garton, S. Nim, T. A. Stone, K. E. Wang, C. M. Deber, P. M. Kim, Proc. Natl. Acad. Sci. USA 2018, 115, 1505.

[87]  G. M. Cragg, D. J. Newman, Biochim. Biophys. Acta, Gen. Subj. 2013, 1830, 3670.
         | Crossref | GoogleScholarGoogle Scholar |

[88]  G. Bulaj, O. Buczek, I. Goodsell, E. C. Jimenez, J. Kranski, J. S. Nielsen, J. E. Garrett, B. M. Olivera, Proc. Natl. Acad. Sci. USA 2003, 100, 14562.
         | Crossref | GoogleScholarGoogle Scholar |

[89]  M. S. Wallace, Expert Rev. Neurother. 2006, 6, 1423.
         | Crossref | GoogleScholarGoogle Scholar |

[90]  K. Matinkhoo, A. Pryyma, M. Todorovic, B. O. Patrick, D. M. Perrin, J. Am. Chem. Soc. 2018, 140, 6513.

[91]  G. Petzold, E. S. Fischer, N. H. Thomä, Nature 2016, 532, 127.
         | Crossref | GoogleScholarGoogle Scholar |

[92]  T. Rodrigues, D. Reker, P. Schneider, G. Schneider, Nat. Chem. 2016, 8, 531.
         | Crossref | GoogleScholarGoogle Scholar |

[93]  D. A. Erlanson, S. W. Fesik, R. E. Hubbard, W. Jahnke, H. Jhoti, Nat. Rev. Drug Discov. 2016, 15, 605.
         | Crossref | GoogleScholarGoogle Scholar |

[94]  K. C. Morrison, P. J. Hergenrother, Nat. Prod. Rep. 2014, 31, 6.
         | Crossref | GoogleScholarGoogle Scholar |

[95]  S. L. Schreiber, Science 2000, 287, 1964.
         | Crossref | GoogleScholarGoogle Scholar |

[96]  M. D. Burke, S. L. Schreiber, Angew. Chem. Int. Ed. 2004, 43, 46.
         | Crossref | GoogleScholarGoogle Scholar |

[97]  G. Moura-Letts, C. M. DiBlasi, R. A. Bauer, D. S. Tan, Proc. Natl. Acad. Sci. USA 2011, 108, 6745.
         | Crossref | GoogleScholarGoogle Scholar |

[98]  J. Barjau, G. Schnakenburg, S. R. Waldvogel, Angew. Chem. Int. Ed. 2011, 50, 1415.
         | Crossref | GoogleScholarGoogle Scholar |

[99]  B. Z. Stanton, L. F. Peng, N. Maloof, K. Nakai, X. Wang, J. L. Duffner, K. M. Taveras, J. M. Hyman, S. W. Lee, A. N. Koehler, J. K. Chen, J. L. Fox, A. Mandinova, S. L. Schreiber, Nat. Chem. Biol. 2009, 5, 154.
         | Crossref | GoogleScholarGoogle Scholar |

[100]  J. E. Bradner, O. M. McPherson, R. Mazitschek, D. Barnes-Seeman, J. P. Shen, J. Dhaliwal, K. E. Stevenson, J. L. Duffner, S. B. Park, D. S. Neuberg, P. Nghiem, S. L. Schreiber, A. N. Koehler, Chem. Biol. 2006, 13, 493.
         | Crossref | GoogleScholarGoogle Scholar |

[101]  E. R. Zartler, ACS Med. Chem. Lett. 2014, 5, 952.
         | Crossref | GoogleScholarGoogle Scholar |

[102]  G. M. Keserű, D. A. Erlanson, G. G. Ferenczy, M. M. Hann, C. W. Murray, S. D. Pickett, J. Med. Chem. 2016, 59, 8189.
         | Crossref | GoogleScholarGoogle Scholar |

[103]  G. M. Keserű, M. M. Hann, Future Med. Chem. 2017, 9, 1457.
         | Crossref | GoogleScholarGoogle Scholar |

[104]  P. J. Hajduk, J. Greer, Nat. Rev. Drug Discov. 2007, 6, 211.
         | Crossref | GoogleScholarGoogle Scholar |

[105]  M. Congreve, R. Carr, C. Murray, H. Jhoti, Drug Discov. Today 2003, 8, 876.
         | Crossref | GoogleScholarGoogle Scholar |

[106]  B. J. Davis, S. D. Roughley, in Annual Reports in Medicinal Chemistry (Ed. R. A. Goodnow) 2017, Vol. 50, pp. 371–440 (Academic Press: San Diego, CA).

[107]  G. Bollag, J. Tsai, J. Zhang, C. Zhang, P. Ibrahim, K. Nolop, P. Hirth, Nat. Rev. Drug Discov. 2012, 11, 873.
         | Crossref | GoogleScholarGoogle Scholar |

[108]  J. Tsai, J. T. Lee, W. Wang, J. Zhang, H. Cho, S. Mamo, R. Bremer, S. Gillette, J. Kong, N. K. Haass, K. Sproesser, L. Li, K. S. M. Smalley, D. Fong, Y.-L. Zhu, A. Marimuthu, H. Nguyen, B. Lam, J. Liu, I. Cheung, J. Rice, Y. Suzuki, C. Luu, C. Settachatgul, R. Shellooe, J. Cantwell, S.-H. Kim, J. Schlessinger, K. Y. J. Zhang, B. L. West, B. Powell, G. Habets, C. Zhang, P. N. Ibrahim, P. Hirth, D. R. Artis, M. Herlyn, G. Bollag, Proc. Natl. Acad. Sci. USA 2008, 105, 3041.
         | Crossref | GoogleScholarGoogle Scholar |

[109]  A. J. Souers, J. D. Leverson, E. R. Boghaert, S. L. Ackler, N. D. Catron, J. Chen, B. D. Dayton, H. Ding, S. H. Enschede, W. J. Fairbrother, D. C. S. Huang, S. G. Hymowitz, S. Jin, S. L. Khaw, P. J. Kovar, L. T. Lam, J. Lee, H. L. Maecker, K. C. Marsh, K. D. Mason, M. J. Mitten, P. M. Nimmer, A. Oleksijew, C. H. Park, C.-M. Park, D. C. Phillips, A. W. Roberts, D. Sampath, J. F. Seymour, M. L. Smith, G. M. Sullivan, S. K. Tahir, C. Tse, M. D. Wendt, Y. Xiao, J. C. Xue, H. Zhang, R. A. Humerickhouse, S. H. Rosenberg, S. W. Elmore, Nat. Med. 2013, 19, 202.
         | Crossref | GoogleScholarGoogle Scholar |

[110]  V. Velvadapu, B. T. Farmer, A. B. Reitz, in The Practice of Medicinal Chemistry (Fourth Edition) (Eds D. Aldous, P. Raboisson, D. Rognan) 2015, pp. 161–180 (Academic Press: San Diego, CA).

[111]  B. Over, S. Wetzel, C. Grütter, Y. Nakai, S. Renner, D. Rauh, H. Waldmann, Nat. Chem. 2013, 5, 21.
         | Crossref | GoogleScholarGoogle Scholar |

[112]  S. M. Cohen, Acc. Chem. Res. 2017, 50, 2007.
         | Crossref | GoogleScholarGoogle Scholar |

[113]  J. Li, T. Yakushi, F. Parlati, A. L. Mackinnon, C. Perez, Y. Ma, K. P. Carter, S. Colayco, G. Magnuson, B. Brown, K. Nguyen, S. Vasile, E. Suyama, L. H. Smith, E. Sergienko, A. B. Pinkerton, T. D. Y. Chung, A. E. Palmer, I. Pass, S. Hess, S. M. Cohen, R. J. Deshaies, Nat. Chem. Biol. 2017, 13, 486.
         | Crossref | GoogleScholarGoogle Scholar |

[114]  C. Perez, J. Li, F. Parlati, M. Rouffet, Y. Ma, A. L. Mackinnon, T.-F. Chou, R. J. Deshaies, S. M. Cohen, J. Med. Chem. 2017, 60, 1343.
         | Crossref | GoogleScholarGoogle Scholar |

[115]  J. A. Jacobsen, J. L. Fullagar, M. T. Miller, S. M. Cohen, J. Med. Chem. 2011, 54, 591.
         | Crossref | GoogleScholarGoogle Scholar |

[116]  C. Gaul, S. J. Danishefsky, Tetrahedron Lett. 2002, 43, 9039.
         | Crossref | GoogleScholarGoogle Scholar |

[117]  C. Gaul, J. T. Njardarson, S. J. Danishefsky, J. Am. Chem. Soc. 2003, 125, 6042.
         | Crossref | GoogleScholarGoogle Scholar |

[118]  C. Gaul, J. T. Njardarson, D. Shan, D. C. Dorn, K.-D. Wu, W. P. Tong, X.-Y. Huang, M. A. S. Moore, S. J. Danishefsky, J. Am. Chem. Soc. 2004, 126, 11326.
         | Crossref | GoogleScholarGoogle Scholar |

[119]  J. T. Njardarson, C. Gaul, D. Shan, X.-Y. Huang, S. J. Danishefsky, J. Am. Chem. Soc. 2004, 126, 1038.
         | Crossref | GoogleScholarGoogle Scholar |

[120]  N. Lecomte, J. T. Njardarson, P. Nagorny, G. Yang, R. Downey, O. Ouerfelli, M. A. S. Moore, S. J. Danishefsky, Proc. Natl. Acad. Sci. USA 2011, 108, 15074.
         | Crossref | GoogleScholarGoogle Scholar |

[121]  T. Oskarsson, P. Nagorny, I. J. Krauss, L. Perez, M. Mandal, G. Yang, O. Ouerfelli, D. Xiao, M. A. S. Moore, J. Massagué, S. J. Danishefsky, J. Am. Chem. Soc. 2010, 132, 3224.
         | Crossref | GoogleScholarGoogle Scholar |

[122]  A. R. Patel, F. Liu, Aust. J. Chem. 2015, 68, 50.
         | Crossref | GoogleScholarGoogle Scholar |

[123]  A. R. Patel, G. Ball, L. Hunter, F. Liu, Org. Biomol. Chem. 2013, 11, 3781.
         | Crossref | GoogleScholarGoogle Scholar |

[124]  A. R. Patel, F. Liu, Tetrahedron 2013, 69, 744.
         | Crossref | GoogleScholarGoogle Scholar |

[125]  A. R. Patel, L. Hunter, M. M. Bhadbhade, F. Liu, Eur. J. Org. Chem. 2014, 2014, 2584.
         | Crossref | GoogleScholarGoogle Scholar |

[126]  A. Hardianto, F. Liu, S. Ranganathan, J. Chem. Inf. Model. 2018, 58, 511.
         | Crossref | GoogleScholarGoogle Scholar |

[127]  A. Hardianto, M. Yusuf, F. Liu, S. Ranganathan, BMC Bioinformatics 2017, 18, 572.
         | Crossref | GoogleScholarGoogle Scholar |

[128]  A. R. Patel, A. Hardianto, S. Ranganathan, F. Liu, Org. Biomol. Chem. 2017, 15, 1570.
         | Crossref | GoogleScholarGoogle Scholar |

[129]  A. Hardianto, F. Liu, S. Ranganathan, J. Chem. Inf. Model. 2018, 58, 511.
         | Crossref | GoogleScholarGoogle Scholar |

[130]  X.-G. Hu, L. Hunter, Beilstein J. Org. Chem. 2013, 9, 2696.
         | Crossref | GoogleScholarGoogle Scholar |

[131]  M. R. Scholfield, C. M. V. Zanden, M. Carter, P. S. Ho, Protein Sci. 2013, 22, 139.
         | Crossref | GoogleScholarGoogle Scholar |

[132]  J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu, Chem. Rev. 2014, 114, 2432.
         | Crossref | GoogleScholarGoogle Scholar |

[133]  W. Zhu, J. Wang, S. Wang, Z. Gu, J. L. Aceña, K. Izawa, H. Liu, V. A. Soloshonok, J. Fluor. Chem. 2014, 167, 37.
         | Crossref | GoogleScholarGoogle Scholar |

[134]  Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J. L. Aceña, V. A. Soloshonok, K. Izawa, H. Liu, Chem. Rev. 2016, 116, 422.
         | Crossref | GoogleScholarGoogle Scholar |

[135]  Y. Zhu, J. Han, J. Wang, N. Shibata, M. Sodeoka, V. A. Soloshonok, J. A. S. Coelho, F. D. Toste, Chem. Rev. 2018, 118, 3887.
         | Crossref | GoogleScholarGoogle Scholar |

[136]  P. Kulanthaivel, Y. F. Hallock, C. Boros, S. M. Hamilton, W. P. Janzen, L. M. Ballas, C. R. Loomis, J. B. Jiang, B. Katz, J. R. Steiner, J. Clardy, J. Am. Chem. Soc. 1993, 115, 6452.
         | Crossref | GoogleScholarGoogle Scholar |

[137]  Y. Nishizuka, Nature 1984, 308, 693.
         | Crossref | GoogleScholarGoogle Scholar |

[138]  Y. Nishizuka, Science 1986, 233, 305.
         | Crossref | GoogleScholarGoogle Scholar |

[139]  Y. Nishizuka, Nature 1988, 334, 661.
         | Crossref | GoogleScholarGoogle Scholar |

[140]  D. Bradshaw, C. H. Hill, J. S. Nixon, S. E. Wilkinson, Agents Actions 1993, 38, 135.
         | Crossref | GoogleScholarGoogle Scholar |

[141]  A. Fürstner, O. R. Thiel, J. Org. Chem. 2000, 65, 1738.
         | Crossref | GoogleScholarGoogle Scholar |