Skip to content
Publicly Available Published by De Gruyter May 22, 2012

Structure- and ligand-based drug design approaches for neglected tropical diseases

  • Rafael V. C. Guido , Glaucius Oliva and Adriano D. Andricopulo

Drug discovery has moved toward more rational strategies based on our increasing understanding of the fundamental principles of protein–ligand interactions. Structure- (SBDD) and ligand-based drug design (LBDD) approaches bring together the most powerful concepts in modern chemistry and biology, linking medicinal chemistry with structural biology. The definition and assessment of both chemical and biological space have revitalized the importance of exploring the intrinsic complementary nature of experimental and computational methods in drug design. Major challenges in this field include the identification of promising hits and the development of high-quality leads for further development into clinical candidates. It becomes particularly important in the case of neglected tropical diseases (NTDs) that affect disproportionately poor people living in rural and remote regions worldwide, and for which there is an insufficient number of new chemical entities being evaluated owing to the lack of innovation and R&D investment by the pharmaceutical industry. This perspective paper outlines the utility and applications of SBDD and LBDD approaches for the identification and design of new small-molecule agents for NTDs.


IUPAC Congress, IUPAC Congress, CONGRESS, IUPAC Congress, 43rd, San Juan, Puerto Rico, 2011-07-30–2011-08-07


1 10.4155/fmc.11.83, P. G. Ruminski. Future Med. Chem.3, 1253 (2011).Search in Google Scholar PubMed

2 10.1517/17460441.2011.563297, R. S. Ferreira, R. V. C. Guido, A. D. Andricopulo, G. Oliva. Expert Opin. Drug Discov.6, 481 (2011).Search in Google Scholar PubMed

3 E. Chatelain, J. R. Ioset. Drug Discov. Dev. Ther.5, 175 (2011).Search in Google Scholar

4 10.1371/journal.pone.0010610, J. Cohen, M. S. Dibner, A. Wilson. PLoS One5, e10610 (2010).Search in Google Scholar PubMed PubMed Central

5 10.1371/journal.pntd.0001221, P. H. Jakobsen, M. W. Wang, S. Nwaka. PLoS Negl. Trop. Dis.5, e1221 (2011).Search in Google Scholar PubMed PubMed Central

6 10.1371/journal.pntd.0000440, S. Nwaka, B. Ramirez, R. Brun, L. Maes, F. Douglas, R. Ridley. PLoS Negl. Trop. Dis.3, e440 (2009).Search in Google Scholar PubMed PubMed Central

7 10.1021/jm2012062, L. D. Chiaradia, P. G. A. Martins, M. N. S. Cordeiro, R. V. C. Guido, G. Ecco, A. D. Andricopulo, R. A. Yunes, J. Vernal, R. J. Nunes, H. Terenzi. J. Med. Chem.55, 390 (2012).Search in Google Scholar PubMed

8 10.1590/S0100-40421998000500008, A. D. Andricopulo, R. A. Yunes, R. J. Nunes, A. O. S. Savi, R. Correa, A. B. Cruz, V. Cechinel. Quim. Nova21, 573 (1998).Search in Google Scholar

9 10.2174/138620711797537067, R. V. C. Guido, G. Oliva, A. D. Andricopulo. Comb. Chem. High Throughput Screening14, 830 (2011).Search in Google Scholar PubMed

10 L. Tan, J. Batista, J. Bajorath. Chem. Biol. Drug Des.76, 191 (2010).Search in Google Scholar

11 10.2174/156802610790232251, T. T. Talele, S. A. Khedkar, A. C. Rigby. Curr. Top. Med. Chem.10, 127 (2010).Search in Google Scholar PubMed

12 10.2174/156802609789207064, R. V. C. Guido, G. Oliva. Curr. Top. Med. Chem.9, 824 (2009).Search in Google Scholar PubMed

13 10.1038/nrd2220, P. J. Hajduk, J. Greer. Nat. Rev. Drug Discov.6, 211 (2007).Search in Google Scholar PubMed

14 10.1007/s11030-009-9112-5, L. B. Salum, A. D. Andricopulo. Mol. Divers.13, 277 (2009).Search in Google Scholar PubMed

15 V. Olin-Sandoval, R. Moreno-Sanchez, E. Saavedra. Curr. Drug Targets11, 1614 (2010).10.2174/1389450111009011614Search in Google Scholar PubMed

16 10.1002/anie.200300639, R. L. Krauth-Siegel, H. Bauer, H. Schirmer. Angew. Chem., Int. Ed.44, 690 (2005).Search in Google Scholar PubMed

17 10.1007/s00436-002-0771-8, R. L. Krauth-Siegel, O. Inhoff. Parasitol. Res.90, S77 (2003).Search in Google Scholar PubMed

18 10.1002/cmdc.200900098, S. Patterson, D. C. Jones, E. J. Shanks, J. A. Frearson, I. H. Gilbert, P. G. Wyatt, A. H. Fairlamb. ChemMedChem4, 1341 (2009).Search in Google Scholar PubMed PubMed Central

19 10.1002/cmdc.201000420, C. Eberle, B. S. Lauber, D. Fankhauser, M. Kaiser, R. Brun, R. L. Krauth-Siegel, F. Diederich. ChemMedChem6, 292 (2011).Search in Google Scholar PubMed

20 10.1093/nar/28.1.235, H. M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T. N. Bhat, H. Weissig, I. N. Shindyalov, P. E. Bourne. Nucleic Acids Res.28, 235 (2000).Search in Google Scholar PubMed PubMed Central

21 10.1038/nrg1317, M. Bredel, E. Jacoby. Nat. Rev. Genet.5, 262 (2004).Search in Google Scholar PubMed

22 10.1016/j.drudis.2006.08.013, C. J. Harris, A. P. Stevens. Drug Discov. Today11, 880 (2006).Search in Google Scholar PubMed

23 10.1016/j.drudis.2008.12.005, Y. L. Yang, S. J. Adelstein, A. I. Kassis. Drug Discov. Today14, 147 (2009).Search in Google Scholar

24 10.1097/QCO.0b013e328315cca9, J. H. McKerrow, P. J. Rosenthal, R. Swenerton, P. Doyle. Curr. Opin. Infect. Dis.21, 668 (2008).Search in Google Scholar

25 10.1146/annurev.pathol.1.110304.100151, J. H. McKerrow, C. Caffrey, B. Kelly, P. Loke, M. Sajid. Annu. Rev. Pathol.1, 497 (2006).Search in Google Scholar

26 10.1038/415673a, L. H. Miller, D. I. Baruch, K. Marsh, O. K. Doumbo. Nature415, 673 (2002).Search in Google Scholar

27 10.2174/092986711795328328, C. Teixeira, J. R. B. Gomes, P. Gomes. Curr. Med. Chem.18, 1555 (2011).Search in Google Scholar

28 10.1016/S0968-0896(99)00008-5, J. H. McKerrow, J. C. Engel, C. R. Caffrey. Bioorg. Med. Chem.7, 639 (1999).Search in Google Scholar

29 10.1002/cmdc.201000449, V. Ehmke, C. Heindl, M. Rottmann, C. Freymond, W. B. Schweizer, R. Brun, A. Stich, T. Schirmeister, F. Diederich. ChemMedChem6, 273 (2011).Search in Google Scholar PubMed PubMed Central

30 10.1021/ja710254m, K. Brak, P. S. Doyle, J. H. McKerrow, J. A. Ellman. J. Am. Chem. Soc.130, 6404 (2008).Search in Google Scholar PubMed PubMed Central

31 10.1021/jm901069a, B. T. Mott, R. S. Ferreira, A. Simeonov, A. Jadhav, K. K. H. Ang, W. Leister, M. Shen, J. T. Silveira, P. S. Doyle, M. R. Arkin, J. H. McKerrow, J. Inglese, C. P. Austin, C. J. Thomas, B. K. Shoichet, D. J. Maloney. J. Med. Chem.53, 52 (2010).Search in Google Scholar PubMed PubMed Central

32 10.1080/14756360701810322, R. V. C. Guido, G. H. Trossini, M. S. Castilho, G. Oliva, E. I. Ferreira, A. D. Andricopulo. J. Enzyme Inhib. Med. Chem.23, 964 (2008).Search in Google Scholar PubMed

33 10.1016/j.jmgm.2006.09.003, K. M. Honorio, R. C. Garratt, I. Polikarpov, A. D. Andricopulo. J. Mol. Graphics Model.25, 921 (2007).Search in Google Scholar PubMed

34 10.1002/qsar.200710139, R. V. C. Guido, M. S. Castilho, S. G. R. Mota, G. Oliva, A. D. Andricopulo. QSAR Comb. Sci.27, 768 (2008).Search in Google Scholar

35 10.1016/j.chroma.2005.10.063, C. L. Cardoso, V. V. Lima, A. Zottis, G. Oliva, A. D. Andricopulo, I. W. Wainer, R. Moaddel, Q. B. Cass. J. Chromatogr., A1120, 151 (2006).Search in Google Scholar PubMed

36 10.1590/S0103-50532010001000008, R. V. C. Guido, C. L. Cardoso, M. C. de Moraes, A. D. Andricopulo, Q. B. Cass, G. Oliva. J. Braz. Chem. Soc.21, 1845 (2010).Search in Google Scholar

37 10.1039/c0md00253d, K. N. de Oliveira, L. D. Chiaradia, P. G. A. Martins, A. Mascarello, M. N. S. Cordeiro, R. V. C. Guido, A. D. Andricopulo, R. A. Yunes, R. J. Nunes, J. Vernal, H. Terenzi. MedChemComm2, 500 (2011).Search in Google Scholar

38 10.1016/j.bmc.2010.04.051, A. Mascarello, L. D. Chiaradia, J. Vernal, A. Villarino, R. V. Guido, P. Perizzolo, V. Poirier, D. Wong, P. G. Martins, R. J. Nunes, R. A. Yunes, A. D. Andricopulo, Y. Av-Gay, H. Terenzi. Bioorg. Med. Chem.18, 3783 (2010).Search in Google Scholar PubMed

39 10.1021/ja00226a005, R. D. Cramer, D. E. Patterson, J. D. Bunce. J. Am. Chem. Soc.110, 5959 (1988).Search in Google Scholar PubMed

40 R. D. Cramer 3rd, D. E. Patterson, J. D. Bunce. Prog. Clin. Biol. Res.291, 161 (1989).Search in Google Scholar

41 10.1021/jm00050a010, G. Klebe, U. Abraham, T. Mietzner. J. Med. Chem.37, 4130 (1994).Search in Google Scholar PubMed

42 10.1023/A:1008047919606, G. Klebe, U. Abraham. J. Comput.-Aided Mol. Des.13, 1 (1999).Search in Google Scholar

43 10.2174/138161210792389225, I. Garcia, Y. Fall, G. Gomez. Curr. Pharm. Des.16, 2666 (2010).Search in Google Scholar PubMed

44 I. Garcia, Y. Fall, G. Gomez. Curr. Bioinf.6, 215 (2011).10.2174/1574893611106020215Search in Google Scholar

45 K. K. Roy, S. S. Bhunia, A. K. Saxena. Chem. Biol. Drug Des.78, 483 (2011).10.1111/j.1747-0285.2011.01158.xSearch in Google Scholar

46 10.1007/s10822-009-9278-z, A. H. Xie, S. Odde, S. Prasanna, R. J. Doerksen. J. Comput.-Aided Mol. Des.23, 431 (2009).Search in Google Scholar PubMed

47 10.1021/ci700453j, R. V. C. Guido, G. Oliva, C. A. Montanari, A. D. Andricopulo. J. Chem. Inf. Model.48, 918 (2008).Search in Google Scholar PubMed

48 10.1016/j.jmgm.2009.03.001, G. H. Trossini, R. V. Guido, G. Oliva, E. I. Ferreira, A. D. Andricopulo. J. Mol. Graph. Model.28, 3 (2009).Search in Google Scholar PubMed

49 10.1016/j.bmcl.2011.04.015, P. B. McKay, M. B. Peters, G. Carta, C. T. Flood, E. Dempsey, A. Bell, C. Berry, D. G. Lloyd, D. Fayne. Bioorg. Med. Chem. Lett.21, 3335 (2011).Search in Google Scholar PubMed

50 10.1016/j.bmc.2010.05.077, G. F. Ruda, G. Campbell, V. P. Alibu, M. P. Barrett, R. Brenk, I. H. Gilbert. Bioorg. Med. Chem.18, 5056 (2010).Search in Google Scholar PubMed PubMed Central

51 10.1021/jm7016144, M. Jacobsson, M. Garedal, J. Schultz, A. Karlen. J. Med. Chem.51, 2777 (2008).Search in Google Scholar PubMed

52 10.1021/jm0505765, P. V. Desai, A. Patny, J. Gut, P. J. Rosenthal, B. Tekwani, A. Srivastava, M. Avery. J. Med. Chem.49, 1576 (2006).Search in Google Scholar PubMed

53 10.1016/j.bmc.2010.01.022, M. S. Castilho, M. P. Postigo, H. M. Pereira, G. Oliva, A. D. Andricopulo. Bioorg. Med. Chem.18, 1421 (2010).Search in Google Scholar PubMed

54 10.1590/S0103-50532011000300024, M. P. Postigo, R. Krogh, M. F. Terni, H. M. Pereira, G. Oliva, M. S. Castilho, A. D. Andricopulo. J. Braz. Chem. Soc.22, 583 (2011).Search in Google Scholar

55 10.1021/ci100128k, M. P. Postigo, R. V. Guido, G. Oliva, M. S. Castilho, R. P. I. da, J. F. de Albuquerque, A. D. Andricopulo. J. Chem. Inf. Model.50, 1693 (2010).Search in Google Scholar PubMed

Online erschienen: 2012-5-22
Erschienen im Druck: 2012-5-22

© 2013 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 3.6.2023 from
Scroll to top button