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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Review Article

Chemical Intuition in Drug Design and Discovery

Author(s): Júlia G.B. Pedreira, Lucas S. Franco and Eliezer J. Barreiro*

Volume 19, Issue 19, 2019

Page: [1679 - 1693] Pages: 15

DOI: 10.2174/1568026619666190620144142

Price: $65

Abstract

The medicinal chemist plays the most important role in drug design, discovery and development. The primary goal is to discover leads and optimize them to develop clinically useful drug candidates. This process requires the medicinal chemist to deal with large sets of data containing chemical descriptors, pharmacological data, pharmacokinetics parameters, and in silico predictions. The modern medicinal chemist has a large number of tools and technologies to aid him in creating strategies and supporting decision-making. Alongside with these tools, human cognition, experience and creativity are fundamental to drug research and are important for the chemical intuition of medicinal chemists. Therefore, fine-tuning of data processing and in-house experience are essential to reach clinical trials. In this article, we will provide an expert opinion on how chemical intuition contributes to the discovery of drugs, discuss where it is involved in the modern drug discovery process, and demonstrate how multidisciplinary teams can create the optimal environment for drug design, discovery, and development.

Keywords: Chemical Intuition, Medicinal Chemistry, Drug Discovery, Lead Optimization, Structure-Activity Relationship, Decision-making, History of Drug Discovery.

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[1]
Lombando, F.; Waters, N.J. Drug design from the ADME/PK perspective: Does chemical intuition suffice in multifaceted drug discovery? Curr. Top. Med. Chem., 2011, 11(4), 331-333.
[http://dx.doi.org/10.2174/156802611794480936] [PMID: 21320061]
[2]
Gomez, L. Decision making in medicinal chemistry: The power of our intuition. ACS Med. Chem. Lett., 2018, 9(10), 956-958.
[http://dx.doi.org/10.1021/acsmedchemlett.8b00359] [PMID: 30344897]
[3]
Lombardino, J.G.; Lowe, J.A., III The role of the medicinal chemist in drug discovery--Then and now. Nat. Rev. Drug Discov., 2004, 3(10), 853-862.
[http://dx.doi.org/10.1038/nrd1523] [PMID: 15459676]
[4]
Campbell, I.B.; Macdonald, S.J.F.; Procopiou, P.A. Medicinal chemistry in drug discovery in big pharma: Past, present and future. Drug Discov. Today, 2018, 23(2), 219-234.
[http://dx.doi.org/10.1016/j.drudis.2017.10.007] [PMID: 29031621]
[5]
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(9), 605-619.
[http://dx.doi.org/10.1038/nrd.2016.109] [PMID: 27417849]
[6]
Duarte, C.D.; Barreiro, E.J.; Fraga, C.A. Privileged structures: A useful concept for the rational design of new lead drug candidates. Mini Rev. Med. Chem., 2007, 7(11), 1108-1119.
[http://dx.doi.org/10.2174/138955707782331722] [PMID: 18045214]
[7]
Amaro, R.E.; Li, W.W. Emerging methods for ensemble-based virtual screening. Curr. Top. Med. Chem., 2010, 10(1), 3-13.
[http://dx.doi.org/10.2174/156802610790232279] [PMID: 19929833]
[8]
Hopkins, A.L.; Polinsky, A. Knowledge and Intelligence in Drug Design. Ann. Rep. Med. Chem.Academic Press, 2006, Vol. 41, 425-437.
[9]
Li, J.J. Blockbuster Drugs: The rise and decline of the pharmaceutical industry, 1st ed; Li, J.J., Ed.; Oxford University Press, 2014, Vol. 52, p. 240.
[10]
Fischer, E. Einfluss der configuration auf die wirkung der enzyme. Ber. Dtsch. Chem. Ges., 1894, 27, 2985-2993.
[http://dx.doi.org/10.1002/cber.18940270364]
[11]
Lichtenthaler, F.W. 100 Years“Schlüssel-Schloss-Prinzip”: What made emil fischer use this analogy? Angew. Chem. Int. Ed. Engl., 1995, 33, 2364-2374.
[http://dx.doi.org/10.1002/anie.199423641]
[12]
Campbell, S.F. Molecular recognition and drug design. Quim. Nova, 1991, 14, 195-203.
[13]
Winau, F.; Westphal, O.; Winau, R. Paul Ehrlich--In search of the magic bullet. Microbes Infect., 2004, 6(8), 786-789.
[http://dx.doi.org/10.1016/j.micinf.2004.04.003] [PMID: 15207826]
[14]
Strebhardt, K.; Ullrich, A. Paul Ehrlich’s magic bullet concept: 100 years of progress. Nat. Rev. Cancer, 2008, 8(6), 473-480.
[http://dx.doi.org/10.1038/nrc2394] [PMID: 18469827]
[15]
Ehrlich, P. About the ultrastructure of mast cells in the human iris In:Virchow's Archive B; Springer-Verlag. , 1972, Volume 11 Issue 1, pp. 358-375.
[http://dx.doi.org/10.1007/BF02889416]
[16]
Ehrlich, P. Die side chain theory and your opp. In:Muenchener medical weekly; Germany, 1901, pp. 2123-2124.
[17]
Ehrlich, P. Chemotherapeutics: Scientific principles, methods and results. Lancet, 1913, 182, 445-451.
[18]
Riethmiller, S. From Atoxyl to Salvarsan: Searching for the magic bullet. Chemotherapy, 2005, 51(5), 234-242.
[http://dx.doi.org/10.1159/000087453] [PMID: 16103665]
[19]
Sepkowitz, K.A. One hundred years of Salvarsan. N. Engl. J. Med., 2011, 365(4), 291-293.
[http://dx.doi.org/10.1056/NEJMp1105345] [PMID: 21793743]
[20]
Thomas, H.W. Some experiments in the treatment of trrypanosomiasis. BMJ, 1905, 1(2317), 1140-1143.
[http://dx.doi.org/10.1136/bmj.1.2317.1140] [PMID: 20762118]
[21]
Nichols, H.J.; Fordyce, J.A. The treatment of syphilis with preparations of Ehrlich-Hata. JAMA, 1910, 55(14), 1171-1178.
[http://dx.doi.org/10.1001/jama.1910.04330140015006]
[22]
Ehrlich, P. About bladder disorders after use of the drug 606. Vienna. Klin. Wochenschr., 1910, 23, 1131.
[23]
Ahlquist, R.P. A study of the adrenotropic receptors. Am. J. Physiol., 1948, 153(3), 586-600.
[http://dx.doi.org/10.1152/ajplegacy.1948.153.3.586] [PMID: 18882199]
[24]
Ahlquist, R.P. Adrenergic receptors: A personal and practical view. Perspect. Biol. Med., 1973, 17(1), 119-122.
[http://dx.doi.org/10.1353/pbm.1973.0047] [PMID: 4148041]
[25]
Black, J.W. Ahlquist and the development of beta-adrenoceptor antagonists. Postgrad. Med. J., 1976, 52(Suppl. 4), 11-13.
[PMID: 9627]
[26]
Bylund, D.B. Alpha- and beta-adrenergic receptors: Ahlquist’s landmark hypothesis of a single mediator with two receptors. Am. J. Physiol. Endocrinol. Metab., 2007, 293(6), E1479-E1481.
[http://dx.doi.org/10.1152/ajpendo.00664.2007] [PMID: 17957033]
[27]
Powell, C.E.; Slater, I.H.; LeCompte, L.; Waddell, J.E. Blocking of inhibitory adrenergic receptors by a dichloro analog of isoproterenol. J. Pharmacol. Exp. Ther., 1958, 122(4), 480-488.
[PMID: 13539775]
[28]
Black, J. Drugs from emasculated hormones: the principle of syntopic antagonism. Science, 1989, 245(4917), 486-493.
[http://dx.doi.org/10.1126/science.2569237] [PMID: 2569237]
[29]
Le Count, D.J. Chronicles of drug discovery. In: .Atenolol; Brindra, J.S.; Lednicer, D., Eds.; John Wiley & Sons: New York, 1984, Vol. 1, pp. 113-132.
[30]
Black, J.W.; Stephenson, J.S. Pharmacology of a new adrenergic beta-receptor-blocking compound (Nethalide). Lancet, 1962, 2(7251), 311-314.
[http://dx.doi.org/10.1016/S0140-6736(62)90103-4] [PMID: 13869657]
[31]
Dornhorst, A.C.; Robinson, B.F. Clinical pharmacology of a beta-adrenergic-blocking agent (Nethalide). Lancet, 1962, 2(7251), 314-316.
[http://dx.doi.org/10.1016/S0140-6736(62)90104-6] [PMID: 13887414]
[32]
Black, J.W.; Crowther, A.F.; Shanks, R.G.; Smith, L.H.; Dornhorst, A.C. A New Adrenergic. Lancet, 1964, 1(7342), 1080-1081.
[http://dx.doi.org/10.1016/S0140-6736(64)91275-9] [PMID: 14132613]
[33]
Chester, E.H.; Schwartz, H.J.; Fleming, G.M. Adverse effect of propranolol on airway function in nonasthmatic chronic obstructive lung disease. Chest, 1981, 79(5), 540-544.
[http://dx.doi.org/10.1378/chest.79.5.540] [PMID: 7014121]
[34]
Wermuth, C.G. The practice of medicinal chemistry. In: Strategies in the Search of Lead Compounds or original working hypotheses; Wermuth, C.G., Ed.; Elsevier: London, 2003, pp. 67-90.
[http://dx.doi.org/10.1016/B978-0-12-374194-3.00006-8]
[35]
Black, J. Drugs from emasculated hormones: the principle of syntopic antagonism. Science, 1989, 245(4917), 486-493.
[http://dx.doi.org/10.1126/science.2569237] [PMID: 2569237]
[36]
Ash, A.S.F.; Schild, H.O.; Black, J.W. Receptors mediating some actions of histamine. 1966. Br. J. Pharmacol., 1997, 120(4)(Suppl), 302-314.
[http://dx.doi.org/10.1111/j.1476-5381.1997.tb06811.x] [PMID: 9142412]
[37]
Ganellin, R. 1980 award in medicinal chemistry: Medicinal chemistry and dynamic structure-activity analysis in the discovery of drugs acting at histamine H2 receptors. J. Med. Chem., 1981, 24(8), 913-920.
[http://dx.doi.org/10.1021/jm00140a001] [PMID: 6120235]
[38]
Durant, G.J.; Parsons, M.E.; Black, J.W. Potential histamine H2-receptor antagonists. 2. N-alpha-Guanylhistamine. J. Med. Chem., 1975, 18(8), 830-833.
[http://dx.doi.org/10.1021/jm00242a014] [PMID: 240023]
[39]
Brimblecombe, R.W.; Ganellin, C.R. Cimetidine and Other Histamine H2-Receptor Antagonists. In:Drug Discovery and Development; Humana Press: Totowa, NJ, 1987, pp. 353-385.
[http://dx.doi.org/10.1007/978-1-4612-4828-6_13]
[40]
Black, J.W.; Duncan, W.A.M.; Durant, C.J.; Ganellin, C.R.; Parsons, E.M. Definition and antagonism of histamine H2-receptors. Nature, 1972, 236(5347), 385-390.
[http://dx.doi.org/10.1038/236385a0] [PMID: 4401751]
[41]
Wyllie, J.H.; Hesselbo, T.; Black, J.W. Effects in man of histamine H2-receptor blockade by burimamide. Lancet, 1972, 2(7787), 1117-1120.
[http://dx.doi.org/10.1016/S0140-6736(72)92719-5] [PMID: 4117206]
[42]
Black, J.W.; Duncan, W.A.M.; Emmett, J.C.; Ganellin, C.R.; Hesselbo, T.; Parsons, M.E.; Wyllie, J.H. Metiamide--an orally active histamine H2-receptor antagonist. Agents Actions, 1973, 3(3), 133-137.
[http://dx.doi.org/10.1007/BF01965723] [PMID: 4150324]
[43]
Black, J.W.; Durant, G.J.; Emmett, J.C.; Ganellin, C.R. Sulphur-methylene isosterism in the development of metiamide, a new histamine H2-receptor antagonist. Nature, 1974, 248(5443), 65-67.
[http://dx.doi.org/10.1038/248065a0] [PMID: 4150456]
[44]
Durant, G.J.; Emmett, J.C.; Ganellin, C.R.; Miles, P.D.; Parsons, M.E.; Prain, H.D.; White, G.R. Cyanoguanidine-thiourea equivalence in the development of the histamine H2-receptor antagonist, cimetidine. J. Med. Chem., 1977, 20(7), 901-906.
[http://dx.doi.org/10.1021/jm00217a007] [PMID: 17751]
[45]
Hawgood, B.J. Maurício Rocha e Silva MD: snake venom, bradykinin and the rise of autopharmacology. Toxicon, 1997, 35(11), 1569-1580.
[http://dx.doi.org/10.1016/S0041-0101(97)00008-1] [PMID: 9428104]
[46]
Silva, M.R.; Beraldo, W.T.; Rosenfeld, G. Bradykinim, A hypotensive and smooth muscle stimulatiinh factor released from plasma globulin by snake venoms and by trypsin. Am. J. Physiol. Content, 1949, 156, 261-273.
[http://dx.doi.org/10.1152/ajplegacy.1949.156.2.261]
[47]
Elliott, D.F. The discovery and characterization of bradykinin. In: Bradykinin, Kallidin and Kallikrein; Erdös, E.G.; Wilde, A.F., Eds.; Springer Berlin Heidelberg: Berlin, Heidelberg, 1970, pp. 7-13.
[http://dx.doi.org/10.1007/978-3-642-46222-1_2]
[48]
Downey, P. Profile of sérgio ferreira. Proc. Natl. Acad. Sci. USA, 2008, 105(49), 19035-19037.
[http://dx.doi.org/10.1073/pnas.0811464106] [PMID: 19057012]
[49]
Ferreira, S.H. A bradykinin-potentiating factor (BPF) present in the venom of bothrops jararaca. Br. J. Pharmacol. Chemother., 1965, 24, 163-169.
[http://dx.doi.org/10.1111/j.1476-5381.1965.tb02091.x] [PMID: 14302350]
[50]
Skeggs, L.T., Jr; Kahn, J.R.; Shumway, N.P. The preparation and function of the hypertensin-converting enzyme. J. Exp. Med., 1956, 103(3), 295-299.
[http://dx.doi.org/10.1084/jem.103.3.295] [PMID: 13295487]
[51]
Smith, C.G.; Vane, J.R. The discovery of captopril. FASEB J., 2003, 17(8), 788-789.
[http://dx.doi.org/10.1096/fj.03-0093life] [PMID: 12724335]
[52]
Erdös, E.G. The ACE and I: How ACE inhibitors came to be. FASEB J., 2006, 20(8), 1034-1038.
[http://dx.doi.org/10.1096/fj.06-0602ufm] [PMID: 16770001]
[53]
Cushman, D.W.; Ondetti, M.A. History of the design of captopril and related inhibitors of angiotensin converting enzyme. Hypertension, 1991, 17(4), 589-592.
[http://dx.doi.org/10.1161/01.HYP.17.4.589] [PMID: 2013486]
[54]
Gavras, H.; Brunner, H.R.; Laragh, J.H.; Sealey, J.E.; Gavras, I.; Vukovich, R.A. An angiotensin converting-enzyme inhibitor to identify and treat vasoconstrictor and volume factors in hypertensive patients. N. Engl. J. Med., 1974, 291(16), 817-821.
[http://dx.doi.org/10.1056/NEJM197410172911603] [PMID: 4371298]
[55]
Johnson, J.G.; Black, W.D.; Vukovich, R.A.; Hatch, F.E., Jr; Friedman, B.I.; Blackwell, C.F.; Shenouda, A.N.; Share, L.; Shade, R.E.; Acchiardo, S.R.; Muirhead, E.E. Treatment of patients with severe hypertension by inhibition of angiotensin-converting enzyme. Clin. Sci. Mol. Med. Suppl., 1975, 2, 53s-56s.
[PMID: 1077791]
[56]
Cushman, D.W.; Cheung, H.S.; Sabo, E.F.; Ondetti, M.A. Design of potent competitive inhibitors of angiotensin-converting enzyme. Carboxyalkanoyl and mercaptoalkanoyl amino acids. Biochemistry, 1977, 16(25), 5484-5491.
[http://dx.doi.org/10.1021/bi00644a014] [PMID: 200262]
[57]
Cushman, D.W.; Cheung, H.S.; Sabo, E.F.; Ondetti, M.A. Design of new antihypertensive drugs: Potent and specific inhibitors of angiotensin-converting enzyme. Prog. Cardiovasc. Dis., 1978, 21(3), 176-182.
[http://dx.doi.org/10.1016/0033-0620(78)90023-3] [PMID: 214817]
[58]
Steitz, T.A.; Ludwig, M.L.; Quiocho, F.A.; Lipscomb, W.N. The structure of carboxypeptidase A. J. Biol. Chem., 1967, 242, 4462-4668.
[59]
Jackson, E.K. Goodman & Gilman’s: The pharmacological basis of therapeutics. In: Renin and angiotensin; Brunton, L.S.; Lazo, J.S.; Parker, K.L., Eds.; McGraw Hill: New York, 2006, pp. 789-821.
[60]
Cohen, J. Drug Development: Protease inhibitors: A tale of two companies. Science, 1996, 272, 1882-1883.
[http://dx.doi.org/10.1126/science.272.5270.1882]
[61]
Vagelos, P.R.; Galambos, L. Medicine, science and merck. In:Partners; Cambridge University Press: New York, 2004, pp. 272-275.
[http://dx.doi.org/10.1017/CBO9780511511677.013]
[62]
Navia, M.A.; Fitzgerald, P.M.D.; McKeever, B.M.; Leu, C-T.; Heimbach, J.C.; Herber, W.K.; Sigal, I.S.; Darke, P.L.; Springer, J.P. Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature, 1989, 337(6208), 615-620.
[http://dx.doi.org/10.1038/337615a0] [PMID: 2645523]
[63]
Kuntz, I.D. Structure-based strategies for drug design and discovery. Science, 1992, 257(5073), 1078-1082.
[http://dx.doi.org/10.1126/science.257.5073.1078] [PMID: 1509259]
[64]
Wang, X.; Song, K.; Li, L.; Chen, L. Structure-based drug design strategies and challenges. Curr. Top. Med. Chem., 2018, 18(12), 998-1006.
[http://dx.doi.org/10.2174/1568026618666180813152921] [PMID: 30101712]
[65]
Wang, T.; Wu, M-B.; Zhang, R-H.; Chen, Z-J.; Hua, C.; Lin, J-P.; Yang, L-R. Advances in computational structure-based drug design and application in drug discovery. Curr. Top. Med. Chem., 2016, 16(9), 901-916.
[http://dx.doi.org/10.2174/1568026615666150825142002] [PMID: 26303430]
[66]
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(9), 1646-1657.
[http://dx.doi.org/10.1021/acs.accounts.6b00185] [PMID: 27529781]
[67]
Merino, F.; Raunser, S. Electron cryo-microscopy as a tool for structure-based drug development. Angew. Chem. Int. Ed. Engl., 2017, 56(11), 2846-2860.
[http://dx.doi.org/10.1002/anie.201608432] [PMID: 27860084]
[68]
Brik, A.; Wong, C-H. HIV-1 protease: mechanism and drug discovery. Org. Biomol. Chem., 2003, 1(1), 5-14.
[http://dx.doi.org/10.1039/b208248a] [PMID: 12929379]
[69]
Wlodawer, A. Rational approach to AIDS drug design through structural biology. Annu. Rev. Med., 2002, 53, 595-614.
[http://dx.doi.org/10.1146/annurev.med.53.052901.131947] [PMID: 11818491]
[70]
Lin, J.H.; Drazen, O.; Vacca, J.P. Integration of pharmaceutical discovery and development. The integration of medicinal chemistry, drug metabolism, and pharmaceutical research and development in drug discovery and development: The story of Crixivan®, an HIV protease inhibitor; Borchardt, R.T.; Freidinger, R.M.; Sawyer, T.K; Smith, P.L., Ed.; Kluwer Academic Publishers: New York, 2013, Vol. 11, pp. 233-255.
[71]
Vacca, J.P.; Guare, J.P.; deSolms, S.J.; Sanders, W.M.; Giuliani, E.A.; Young, S.D.; Darke, P.L.; Zugay, J.; Sigal, I.S.; Schleif, W.A. L-687,908, a potent hydroxyethylene-containing HIV protease inhibitor. J. Med. Chem., 1991, 34(3), 1225-1228.
[http://dx.doi.org/10.1021/jm00107a050] [PMID: 2002465]
[72]
Thompson, W.J.; Fitzgerald, P.M.D.; Holloway, M.K.; Emini, E.A.; Darke, P.L.; McKeever, B.M.; Schleif, W.A.; Quintero, J.C.; Zugay, J.A. Synthesis and antiviral activity of a series of HIV-1 protease inhibitors with functionality tethered to the P1 or P1′ phenyl design. J. Med. Chem., 1992, 35, 1685-1701.
[http://dx.doi.org/10.1021/jm00088a003] [PMID: 1588551]
[73]
Vacca, J.P. HIV Protease Inhibitors Useful for the Treatment of Aids. EP 0 541 168 A1 May 12 1993,
[74]
Dorsey, B.D.; Levin, R.B.; McDaniel, S.L.; Vacca, J.P.; Guare, J.P.; Darke, P.L.; Zugay, J.A.; Emini, E.A.; Schleif, W.A.; Quintero, J.C. L-735,524: the design of a potent and orally bioavailable HIV protease inhibitor. J. Med. Chem., 1994, 37(21), 3443-3451.
[http://dx.doi.org/10.1021/jm00047a001] [PMID: 7932573]
[75]
Vacca, J.P.; Dorsey, B.D.; Schleif, W.A.; Levin, R.B.; McDaniel, S.L.; Darke, P.L.; Zugay, J.; Quintero, J.C.; Blahy, O.M.; Roth, E. L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor. Proc. Natl. Acad. Sci. USA, 1994, 91(9), 4096-4100.
[http://dx.doi.org/10.1073/pnas.91.9.4096] [PMID: 8171040]
[76]
Barreiro, E.J.; Kümmerle, A.E.; Fraga, C.A.M. The methylation effect in medicinal chemistry. Chem. Rev., 2011, 111(9), 5215-5246.
[http://dx.doi.org/10.1021/cr200060g] [PMID: 21631125]
[77]
Bazzini, P.; Wermuth, C.G. The practice of medicinal chemistry. In:Substituent Groups; Wermuth, C.G., Ed.; Elsevier: London, 2008, pp. 431-463.
[78]
Capdeville, R.; Buchdunger, E.; Zimmermann, J.; Matter, A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat. Rev. Drug Discov., 2002, 1(7), 493-502.
[http://dx.doi.org/10.1038/nrd839] [PMID: 12120256]
[79]
Schönherr, H.; Cernak, T. Profound methyl effects in drug discovery and a call for new C-H methylation reactions. Angew. Chem. Int. Ed. Engl., 2013, 52(47), 12256-12267.
[http://dx.doi.org/10.1002/anie.201303207] [PMID: 24151256]
[80]
Macarron, R. Critical review of the role of HTS in drug discovery. Drug Discov. Today, 2006, 11(7-8), 277-279.
[http://dx.doi.org/10.1016/j.drudis.2006.02.001] [PMID: 16580969]
[81]
Lambert, G.K.; Duhme-Klair, A-K.; Morgan, T.; Ramjee, M.K. The background, discovery and clinical development of BCR-ABL inhibitors. Drug Discov. Today, 2013, 18(19-20), 992-1000.
[http://dx.doi.org/10.1016/j.drudis.2013.06.001] [PMID: 23769978]
[82]
Zimmermann, J.; Buchdunger, E.; Mett, H.; Meyer, T.; Lydon, N.B.; Traxler, P. Phenylamino-Pyrimidine (PAP) — Derivatives: A new class of potent and highly selective PDGF-receptor autophosphorylation inhibitors. Bioorg. Med. Chem. Lett., 1996, 6, 1221-1226.
[http://dx.doi.org/10.1016/0960-894X(96)00197-7]
[83]
Zimmermann, J.; Buchdunger, E.; Mett, H.; Meyer, T.; Lydon, N.B. Potent and selective inhibitors of the Abl-Kinase: phenylamino-pyrimidine (PAP) Derivatives. Bioorg. Med. Chem. Lett., 1997, 7, 187-192.
[http://dx.doi.org/10.1016/S0960-894X(96)00601-4]
[84]
Buchdunger, E.; Zimmermann, J.; Mett, H.; Meyer, T.; Müller, M.; Regenass, U.; Lydon, N.B. Selective inhibition of the platelet-derived growth factor signal transduction pathway by a protein-tyrosine kinase inhibitor of the 2-phenylaminopyrimidine class. Proc. Natl. Acad. Sci. USA, 1995, 92(7), 2558-2562.
[http://dx.doi.org/10.1073/pnas.92.7.2558] [PMID: 7708684]
[85]
Buchdunger, E.; Zimmermann, J.; Mett, H.; Meyer, T.; Müller, M.; Druker, B.J.; Lydon, N.B. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res., 1996, 56(1), 100-104.
[PMID: 8548747]
[86]
Druker, B.J.; Tamura, S.; Buchdunger, E.; Ohno, S.; Segal, G.M.; Fanning, S.; Zimmermann, J.; Lydon, N.B. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat. Med., 1996, 2(5), 561-566.
[http://dx.doi.org/10.1038/nm0596-561] [PMID: 8616716]
[87]
Schindler, T.; Bornmann, W.; Pellicena, P.; Miller, W.T.; Clarkson, B.; Kuriyan, J. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science, 2000, 289(5486), 1938-1942.
[http://dx.doi.org/10.1126/science.289.5486.1938] [PMID: 10988075]
[88]
Carroll, M.; Ohno-Jones, S.; Tamura, S.; Buchdunger, E.; Zimmermann, J.; Lydon, N.B.; Gilliland, D.G.; Druker, B.J. CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood, 1997, 90(12), 4947-4952.
[PMID: 9389713]
[89]
Lugo, T.G.; Pendergast, A.M.; Muller, A.J.; Witte, O.N. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science, 1990, 247(4946), 1079-1082.
[http://dx.doi.org/10.1126/science.2408149] [PMID: 2408149]
[90]
Kashyap, A.; Singh, P.K.; Silakari, O. Counting on fragment based drug design approach for drug discovery. Curr. Top. Med. Chem., 2018, 18(27), 2284-2293.
[http://dx.doi.org/10.2174/1568026619666181130134250] [PMID: 30499406]
[91]
Ferreira, L.G.; Andricopulo, A.D. From protein structure to small-molecules: Recent advances and applications to fragment-based drug discovery. Curr. Top. Med. Chem., 2017, 17(20), 2260-2270.
[http://dx.doi.org/10.2174/1568026617666170224113437] [PMID: 28240184]
[92]
Hajduk, P.J.; Greer, J. A decade of fragment-based drug design: Strategic advances and lessons learned. Nat. Rev. Drug Discov., 2007, 6(3), 211-219.
[http://dx.doi.org/10.1038/nrd2220] [PMID: 17290284]
[93]
Hajduk, P.J. Fragment-based drug design: How big is too big? J. Med. Chem., 2006, 49(24), 6972-6976.
[http://dx.doi.org/10.1021/jm060511h] [PMID: 17125250]
[94]
Congreve, M.; Carr, R.; Murray, C.; Jhoti, H.A. ‘rule of three’ for fragment-based lead discovery? Drug Discov. Today, 2003, 8(19), 876-877.
[http://dx.doi.org/10.1016/S1359-6446(03)02831-9] [PMID: 14554012]
[95]
Hopkins, A.L.; Groom, C.R.; Alex, A. Ligand efficiency: A useful metric for lead selection. Drug Discov. Today, 2004, 9(10), 430-431.
[http://dx.doi.org/10.1016/S1359-6446(04)03069-7] [PMID: 15109945]
[96]
Deeks, E.D. Venetoclax: First global approval. Drugs, 2016, 76(9), 979-987.
[http://dx.doi.org/10.1007/s40265-016-0596-x] [PMID: 27260335]
[97]
Souers, A.J.; Leverson, J.D.; Boghaert, E.R.; Ackler, S.L.; Catron, N.D.; Chen, J.; Dayton, B.D.; Ding, H.; Enschede, S.H.; Fairbrother, W.J.; Huang, D.C.S.; Hymowitz, S.G.; Jin, S.; Khaw, S.L.; Kovar, P.J.; Lam, L.T.; Lee, J.; Maecker, H.L.; Marsh, K.C.; Mason, K.D.; Mitten, M.J.; Nimmer, P.M.; Oleksijew, A.; Park, C.H.; Park, C-M.; Phillips, D.C.; Roberts, A.W.; Sampath, D.; Seymour, J.F.; Smith, M.L.; Sullivan, G.M.; Tahir, S.K.; Tse, C.; Wendt, M.D.; Xiao, Y.; Xue, J.C.; Zhang, H.; Humerickhouse, R.A.; Rosenberg, S.H.; Elmore, S.W. ABT-199, A potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med., 2013, 19(2), 202-208.
[http://dx.doi.org/10.1038/nm.3048] [PMID: 23291630]
[98]
Wendt, M.D. Discovery of ABT-263, a Bcl-family protein inhibitor: observations on targeting a large protein-protein interaction. Expert Opin. Drug Discov., 2008, 3(9), 1123-1143.
[http://dx.doi.org/10.1517/17460441.3.9.1123] [PMID: 23506184]
[99]
Oltersdorf, T.; Elmore, S.W.; Shoemaker, A.R.; Armstrong, R.C.; Augeri, D.J.; Belli, B.A.; Bruncko, M.; Deckwerth, T.L.; Dinges, J.; Hajduk, P.J.; Joseph, M.K.; Kitada, S.; Korsmeyer, S.J.; Kunzer, A.R.; Letai, A.; Li, C.; Mitten, M.J.; Nettesheim, D.G.; Ng, S.; Nimmer, P.M.; O’Connor, J.M.; Oleksijew, A.; Petros, A.M.; Reed, J.C.; Shen, W.; Tahir, S.K.; Thompson, C.B.; Tomaselli, K.J.; Wang, B.; Wendt, M.D.; Zhang, H.; Fesik, S.W.; Rosenberg, S.H. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature, 2005, 435(7042), 677-681.
[http://dx.doi.org/10.1038/nature03579] [PMID: 15902208]
[100]
Sofia, M.J. Sofosbuvir: The discovery of a curative therapy for the treatment of hepatitis C virus. In:Successful Drug Discovery; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2016, pp. 163-188.
[101]
Götte, M.; Feld, J.J. Direct-acting antiviral agents for hepatitis C: Structural and mechanistic insights. Nat. Rev. Gastroenterol. Hepatol., 2016, 13(6), 338-351.
[http://dx.doi.org/10.1038/nrgastro.2016.60] [PMID: 27147491]
[102]
Bronson, J.; Black, A.; Dhar, M.; Ellsworth, B. Robert Merritt, J. To Market, To Market-2013.Annual Reports in Medicinal Chemistry; Elsevier Inc., 2014, Vol. 49, pp. 437-508.
[103]
Sofia, M.J.; Bao, D.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P.G.; Ross, B.S.; Wang, P.; Zhang, H-R.; Bansal, S.; Espiritu, C.; Keilman, M.; Lam, A.M.; Steuer, H.M.M.; Niu, C.; Otto, M.J.; Furman, P.A. Discovery of a β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J. Med. Chem., 2010, 53(19), 7202-7218.
[http://dx.doi.org/10.1021/jm100863x] [PMID: 20845908]
[104]
Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H.M.M.; Bao, D.; Chang, W.; Espiritu, C.; Bansal, S.; Lam, A.M.; Otto, M.J.; Sofia, M.J.; Furman, P.A. Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J. Biol. Chem., 2010, 285(45), 34337-34347.
[http://dx.doi.org/10.1074/jbc.M110.161802] [PMID: 20801890]
[105]
Cassier, M.; Correa, M. Health Innovation and Social Justice in Brazil.A Consortium in Times of Crisis; 2014-2017. Cassier, M; Correa, M., Ed.; Palgrave Macmillan: Cham, 2019, pp. 135-150.
[http://dx.doi.org/10.1007/978-3-319-76834-2]
[106]
Rabi, J.A. Methods of Manufacture of 2’Deoxy-Beta-LNucleosides. US 7,582,748 B2, 2005.
[107]
Cleary, D.G.; Reynolds, C.J.; Berrey, M.M.; Hindes, R.G.; William, T.S.; Ray, A.S.; Mo, H.; Oliyai, R.; Stefanidis, D.; Pakdaman, R.; Casteel, M.J. Compositions and methods for treating hepatitis C virus. US8,889,159 B2, 2014.
[108]
Ma, H.; Jiang, W-R.; Robledo, N.; Leveque, V.; Ali, S.; Lara-Jaime, T.; Masjedizadeh, M.; Smith, D.B.; Cammack, N.; Klumpp, K.; Symons, J. Characterization of the metabolic activation of hepatitis C virus nucleoside inhibitor β-D-2′-Deoxy-2′-fluoro-2′-C-methylcytidine (PSI-6130) and identification of a novel active 5′-triphosphate species. J. Biol. Chem., 2007, 282(41), 29812-29820.
[http://dx.doi.org/10.1074/jbc.M705274200] [PMID: 17698842]
[109]
McGuigan, C.; Tollerfield, S.M.; Riley, P.A. Synthesis and biological evaluation of some phosphate triester derivatives of the anti-viral drug AraA. Nucleic Acids Res., 1989, 17(15), 6065-6075.
[http://dx.doi.org/10.1093/nar/17.15.6065] [PMID: 2771639]
[110]
Mehellou, Y.; Rattan, H.S.; Balzarini, J. The protide prodrug technology: From the concept to the clinic. J. Med. Chem., 2018, 61(6), 2211-2226.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00734] [PMID: 28792763]
[111]
Mehellou, Y.; Balzarini, J.; McGuigan, C. Aryloxy phosphoramidate triesters: a technology for delivering monophosphorylated nucleosides and sugars into cells. ChemMedChem, 2009, 4(11), 1779-1791.
[http://dx.doi.org/10.1002/cmdc.200900289] [PMID: 19760699]
[112]
McGuigan, C.; Kelleher, M.R.; Perrone, P.; Mulready, S.; Luoni, G.; Daverio, F.; Rajyaguru, S.; Le Pogam, S.; Najera, I.; Martin, J.A.; Klumpp, K.; Smith, D.B. The application of phosphoramidate ProTide technology to the potent anti-HCV compound 4 -′azidocytidine (R1479). Bioorg. Med. Chem. Lett., 2009, 19(15), 4250-4254.
[http://dx.doi.org/10.1016/j.bmcl.2009.05.099] [PMID: 19505826]
[113]
Perrone, P.; Daverio, F.; Valente, R.; Rajyaguru, S.; Martin, J.A.; Lévêque, V.; Le Pogam, S.; Najera, I.; Klumpp, K.; Smith, D.B.; McGuigan, C. First example of phosphoramidate approach applied to a 4′-substituted purine nucleoside (4′-azidoadenosine): conversion of an inactive nucleoside to a submicromolar compound versus hepatitis C virus. J. Med. Chem., 2007, 50(22), 5463-5470.
[http://dx.doi.org/10.1021/jm070362i] [PMID: 17914786]
[114]
Gentile, I.; Borgia, F.; Zappulo, E.; Buonomo, A.R.; Spera, A.M.; Castaldo, G.; Borgia, G. Efficacy and safety of sofosbuvir in the treatment of chronic hepatitis C: The dawn of a new era. Rev. Recent Clin. Trials, 2014, 9(1), 1-7.
[http://dx.doi.org/10.2174/1574887108666131213120354] [PMID: 23859195]
[115]
Sacramento, C.Q.; de Melo, G.R.; de Freitas, C.S.; Rocha, N.; Hoelz, L.V.B.; Miranda, M.; Fintelman-Rodrigues, N.; Marttorelli, A.; Ferreira, A.C.; Barbosa-Lima, G.; Abrantes, J.L.; Vieira, Y.R.; Bastos, M.M.; de Mello Volotão, E.; Nunes, E.P.; Tschoeke, D.A.; Leomil, L.; Loiola, E.C.; Trindade, P.; Rehen, S.K.; Bozza, F.A.; Bozza, P.T.; Boechat, N.; Thompson, F.L.; de Filippis, A.M.B.; Brüning, K.; Souza, T.M.L. The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication. Sci. Rep., 2017, 7, 40920.
[http://dx.doi.org/10.1038/srep40920] [PMID: 28098253]
[116]
Schmutz, J.; Eichenberger, E. Chronicles of drug discovery. In:Clozapine; Brindra, J.S.; Lednicer, D., Eds.; John Wiley & Sons: New York, 1984, Vol. 1, pp. 39-59.
[117]
Menegatti, R.; Cunha, A.C.; Ferreira, V.F.; Perreira, E.F.R.; El-Nabawi, A.; Eldefrawi, A.T.; Albuquerque, E.X.; Neves, G.; Rates, S.M.K.; Fraga, C.A.M.; Barreiro, E.J. Design, synthesis and pharmacological profile of novel dopamine D2 receptor ligands. Bioorg. Med. Chem., 2003, 11(22), 4807-4813.
[http://dx.doi.org/10.1016/S0968-0896(03)00487-5] [PMID: 14556797]
[118]
Neves, G.; Menegatti, R.; Antonio, C.B.; Grazziottin, L.R.; Vieira, R.O.; Rates, S.M.K.; Noël, F.; Barreiro, E.J.; Fraga, C.A.M. Searching for multi-target antipsychotics: Discovery of orally active heterocyclic N-phenylpiperazine ligands of D2-like and 5-HT1A receptors. Bioorg. Med. Chem., 2010, 18(5), 1925-1935.
[http://dx.doi.org/10.1016/j.bmc.2010.01.040] [PMID: 20153652]
[119]
Brown, N.; Jacoby, E. On scaffolds and hopping in medicinal chemistry. Mini Rev. Med. Chem., 2006, 6(11), 1217-1229.
[http://dx.doi.org/10.2174/138955706778742768] [PMID: 17100633]
[120]
Brown, N. Scaffold hopping in medicinal chemistry. In: Methods and Principles in Medicinal Chemistry; Wiley and Sons: New york, 2013.
[http://dx.doi.org/10.1002/9783527665143]

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