Structure-Based Drug Design in Medicinal Chemistry: The Devil is in the Detail

Abstract

Structure-based drug design (SBDD) has become an important concept in medicinal chemistry, and the hypothesis that similar ligands bind in a similar fashion is widely accepted within the medicinal chemistry community. However, there are a number of interesting case studies, some of which are discussed in detail, which highlight that this does not hold true on a comprehensive basis.

Key words

medicinal chemistry - structure-based drug design - hit-to-lead optimization - drug development - X-ray crystallography

• References

• 1 Sertürner FW. A. J. Pharm. 1806; 14: 47
• 2 American Chemical Society International Historic Chemical Landmarks, ‘Discovery and Development of Penicillin’, can be found under http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html.
• 3a Klebe G. Wirkstoffdesign. Entwurf und Wirkung von Arznei­stoffen . Spektrum Akademischer Verlag; Heidelberg: 2009
• 3b Klebe G. Drug Design: Methodology, Concepts, and Mode-of-Action. Springer; Berlin/Heidelberg: 2013
• 4 Acharya C, Coop A, Polli JE, MacKerell AD. Curr. Comput.-Aided Drug Des. 2011; 7: 10
• 5 Black JW, Crowther AF, Shanks RG, Smith LH, Dornhorst AC. Lancet 1964; 283: 1080
• 6 American Chemical Society National Historic Chemical Landmarks, ‘Tagamet®: Discovery of Histamine H2-receptor Antagonists’, can be found under http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/cimetidinetagamet.
• 7a Zhao H, Guo Z. Drug Discovery Today 2009; 14: 516
• 7b Raju TN. K. Lancet 2000; 355: 1022
• 8 Beddell CR, Goodford PJ, Norrington FE, Wilkinson S, Wootton R. Br. J. Pharmacol. 1976; 57: 201
• 9 Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE. Nucleic Acids Res. 2000; 28: 235
• 10 Wlodawer A, Vondrasek J. Annu. Rev. Biophys. Biomol. Struct. 1998; 27: 249
• 11 Hubbard RE. Mol. BioSyst. 2005; 1: 391
• 12 Waring MJ, Arrowsmith J, Leach AR, Leeson PD, Mandrell S, Owen RM, Pairaudeau G, Pennie WD, Pickett SD, Wang J, Wallace O, Weir A. Nat. Rev. Drug Discovery 2015; 14: 475
• 13 Bleicher KH, Böhm H.-J, Müller K, Alanine AI. Nat. Rev. Drug Discovery 2003; 2: 369
• 14a Anderson AC. Chem. Biol. 2003; 10: 787
• 14b Kalyaanamoorthy S, Chen Y.-PP. Drug Discovery Today 2011; 16: 831
• 15 Boström J, Hogner A, Schmitt S. J. Med. Chem. 2006; 49: 6716
• 16 Meyer EF, Botos I, Scapozza L, Zhang D. Perspect. Drug Discovery Des. 1995; 3: 168
• 17a Stubbs MT, Reyda S, Dullweber F, Möller M, Klebe G, Dorsch D, Mederski WW. K. R, Wurziger H. ChemBioChem 2002; 3: 246
• 17b Ciulli A, Lobley CM. C, Tuck KL, Smith AG, Blundell TL, Abell C. Acta Crystallogr., Sect. D 2007; 63: 171
• 18a Steuber H, Zentgraf M, Gerlach C, Sotriffer CA, Heine A, Klebe G. J. Mol. Biol. 2006; 363: 174
• 18b Satoh M, Saburi H, Tanaka T, Matsuura Y, Naitow H, Shimozono R, Yamamoto N, Inoue H, Nakamura N, Yoshizawa Y, Aoki T, Tanimura R, Kunishima N. FEBS Open Bio 2015; 5: 557
• 19a Davis AM, Teague SJ, Kleywegt GJ. Angew. Chem. Int. Ed. 2003; 42: 2718
• 19b Davis AM, St-Gallay SA, Kleywegt GJ. Drug Discovery Today 2008; 13: 831
• 20 Klebe G. Nat. Rev. Drug Discovery 2015; 14: 95
• 21 Mobley DL, Dill KA. Structure 2009; 17: 489
• 22 Badger J, Minor I, Kremer MJ, Oliveira MA, Smith TJ, Griffith JP, Guerin DM, Krishnaswamy S, Luo M, Rossmann MG. Proc. Natl. Acad. Sci. U.S.A. 1988; 85: 3304
• 23 Diana GD, McKinlay MA, Otto MJ, Akullian V, Oglesby C. J. Med. Chem. 1985; 28: 1906
• 24 DeLano WL. The PyMol Molecular Graphics System . DeLano Scientific; San Carlos (CA, USA): 2002
• 25a Shoichet BK, Stroud RM, Santi DV, Kuntz ID, Perry KM. Science 1993; 259: 1445
• 25b Stout TJ, Tondi D, Rinaldi M, Barlocco D, Pecorari P, Santi DV, Kuntz ID, Stroud RM, Shoichet BK, Costi MP. Biochemistry 1999; 38: 1607
• 26a Kuhnert M, Köster H, Bartholomäus R, Park AY, Shahim A, Heine A, Steuber H, Klebe G, Diederich WE. Angew. Chem. Int. Ed. 2015; 54: 2849
• 26b Kuhnert M, Köster H, Bartholomäus R, Park AY, Shahim A, Heine A, Steuber H, Klebe G, Diederich WE. Angew. Chem. 2015; 127: 2891
• 27 Mangani S, Cancian L, Leone R, Pozzi C, Lazzari S, Luciani R, Ferrari S, Costi MP. J. Med. Chem. 2011; 54: 5454
• 28 Blum A, Böttcher J, Heine A, Klebe G, Diederich WE. J. Med. Chem. 2008; 51: 2078
• 29 Böttcher J, Blum A, Heine A, Diederich WE, Klebe G. J. Mol. Biol. 2008; 383: 347
• 30 Blum A, Böttcher J, Dörr S, Heine A, Klebe G, Diederich WE. J. Mol. Biol. 2011; 410: 745
• 31 Das K, Clark AD, Lewi PJ, Heeres J, De Jonge MR, Koymans LM. H, Vinkers HM, Daeyaert F, Ludovici DW, Kukla MJ, de Corte B, Kavash RW, Ho CY, Ye H, Lichtenstein MA, Andries K, Pauwels R, de Béthune M.-P, Boyer PL, Clark P, Hughes SH, Janssen PA. J, Arnold E. J. Med. Chem. 2004; 47: 2550
• 32 Chi G, Manos-Turvey A, O’Connor PD, Johnston JM, Evans GL, Baker EN, Payne RJ, Lott JS, Bulloch EM. M. Biochemistry 2012; 51: 4868
• 33a Vara Prasad JV. N, Pavlovsky A, Para KS, Ellsworth EL, Tummino PJ, Nouhan C, Ferguson D. Bioorg. Med. Chem. Lett. 1996; 6: 1133
• 33b Reich SH, Melnick M, Davies JF, Appelt K, Lewis KK, Fuhry MA, Pino M, Trippe AJ, Nguyen D, Dawson H, Wu B.-W, Musick L, Kosa M, Kahil D, Webber S, Gehlhaar DK, Andrada D, Shetty B. Proc. Natl. Acad. Sci. U.S.A. 1995; 92: 3298
• 34 Stoll V, Stewart KD, Maring CJ, Muchmore S, Giranda V, Gu Y.-GY, Wang G, Chen Y, Sun M, Zhao C, Kennedy AL, Madigan DL, Xu Y, Saldivar A, Kati W, Laver G, Sowin T, Sham HL, Greer J, Kempf D. Biochemistry 2003; 42: 718
• 35 Gassel M, Breitenlechner CB, König N, Huber R, Engh RA, Bossemeyer D. J. Biol. Chem. 2004; 279: 23679