Skip to main content
The AAPS Journal logoLink to The AAPS Journal
. 2005 Dec 7;7(4):E813–E819. doi: 10.1208/aapsj070478

The role of crystallography in drug design

Jeffrey R Deschamps 1,
PMCID: PMC2750950  PMID: 16594633

Abstract

Structure and function are intimately related. Nowhere is this more important than the area of bioactive molecules. It has been shown that the enantioselectivity of an enzyme is directly related to its chirality. X-ray crystallography is the only method for determining the “absolute” configuration of a molecule and is the most comprehensive technique available to determine the structure of any molecule at atomic resolution. Results from crystallographic studies provide unambiguous, accurate, and reliable 3-dimensional structural parameters, which are prerequisites for rational drug design and structure-based functional studies.

Keywords: structure, absolute configuration, opioid, pharmacophore, X-ray diffraction

Full Text

The Full Text of this article is available as a PDF (289.0 KB).

References

  • 1.Griffin JF, Duax WL, editors. Molecular Structure and Biological Activity. New York, NY: Elsevier Biomedical; 1982. [Google Scholar]
  • 2.Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris HR. Identification of 2 related pentapeptides from brain with potent opiate agonist activity. Nature. 1975;258:577–579. doi: 10.1038/258577a0. [DOI] [PubMed] [Google Scholar]
  • 3.Temussi PA, Picone D, Castiglione-Morelli MA, Motta A, Tancredi T. Bioactive conformation of linear peptides in solution: an elusive goal. Biopolymers. 1989;28:91–107. doi: 10.1002/bip.360280112. [DOI] [PubMed] [Google Scholar]
  • 4.Karle IL, Karle J, Mastropaolo D, Camerman A, Camerman N. [Leu-5]enkepalin-4 co-crystallizing conformers with extended backbones that form an anti-parallel beta-sheet. Acta Crystallogr. 1983;B39:625–637. [Google Scholar]
  • 5.Smith D, Griffin JF. Conformation of [Leu-5]enkephalin rrom X-ray-diffraction: features important for recognition at opiate receptor. Science. 1978;199:1214–1216. doi: 10.1126/science.204006. [DOI] [PubMed] [Google Scholar]
  • 6.Aubry A, Birlirakis N, Sakarellos-Daitsiotis M, Sakarellos C, Marraud M. A crystal molecular-conformation of leucine-enkephalin related to the morphine molecule. Biopolymers. 1989;28:27–40. doi: 10.1002/bip.360280106. [DOI] [PubMed] [Google Scholar]
  • 7.Doi M, Tanaka M, Ishida T, et al. Crystal-structures of [Met5] and [(4-bromo)Phe4,Met5]enkephalins: formation of a dimeric antiparallel beta-structure. J Biochem (Tokyo) 1987;101:485–490. doi: 10.1093/oxfordjournals.jbchem.a121934. [DOI] [PubMed] [Google Scholar]
  • 8.Loew GH. Molecular modeling of opioid analgesics. Mod Drug Discovery. 1999;2:24–30. [Google Scholar]
  • 9.SHELXTL [Computer program]. Version 6.10. Madison, Wisconsin: Bruker AXS Inc. 2000.
  • 10.Griffin JF, Langs DA, Smith GD, Blundell TL, Tickle IJ, Bedarkar S. The crystal-structures of [Met5] enkephalin and a third form of [Leu5] enkephalin: observations of a novel pleated β-sheet. Proc Natl Acad Sci USA. 1986;83:3272–3276. doi: 10.1073/pnas.83.10.3272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Deschamps JR, Flippen-Anderson JL, Brine GA, Hayes JP, George C. Boc-tyrosyl-D-alanyl-glycyl-N-methyl-pnenylalanyl-O-methyl-methionine hydrate: a protected analog of metkephamid. Acta Crystallogr. 2002;58E:o13–o15. [Google Scholar]
  • 12.Ishida T, Kenmotsu M, Mino Y, et al. X-Ray diffraction studies of enkephalins: crystal-structure of [(4’-bromo)Phe4,Leu5] enkephalin. Biochem J. 1984;218:677–689. doi: 10.1042/bj2180677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Stezowski JJ, Eckle E, Bajusz SA. Crystal-structure determination for Tyr-d-Nle-Gly-Phe-Nles [Nles=MetCH2CH2CH2CH(NH2)SO3H]: an active synthetic enkephalin analog. J Chem Soc Chem Comm. 1985;11:681–682. doi: 10.1039/c39850000681. [DOI] [Google Scholar]
  • 14.Deschamps JR, George C, Flippen-Anderson JL. [D-Ala2, D-Leu5]-enkephalin (DADLE) Acta Crystallogr. 1996;52:1583–1585. doi: 10.1107/S0108270196000534. [DOI] [PubMed] [Google Scholar]
  • 15.Flippen-Anderson JL, Deschamps JR, Ward KB, George C, Houghten R. The crystal structure of deltakephalin: a δ-selective opioid peptide with a novel β-bend-like conformation. Int J Pept Protein Res. 1994;44:97–104. doi: 10.1111/j.1399-3011.1994.tb00563.x. [DOI] [PubMed] [Google Scholar]
  • 16.Fournie-Zaluski M, Prange T, Pascard C, Roques BP. Enkephalin related fragments: conformational studies of the tetrapeptides Tyr-Gly-Gly-Phe and Gly-Gly-Phe-X (X=Leu, Met) by X-ray and1H NMR spectroscopy. Biochem Biophys Res Commun. 1977;79:1199–1206. doi: 10.1016/0006-291x(77)91133-0. [DOI] [PubMed] [Google Scholar]
  • 17.Flippen-Anderson JL, Deschamps JR, George C, Hruby VJ, Misicka A, Lipkowski AW. Crystal structure of biphalin—multireceptor opioid peptide. J Pept Res. 2002;59:123–133. doi: 10.1034/j.1399-3011.2002.01967.x. [DOI] [PubMed] [Google Scholar]
  • 18.Flippen-Anderson JL, George C, Deschamps JR, Reddy PA, Lewin AH, Brine GA. X-ray structures of a potent δ-receptor selective opioid antagonist and a protected form of the δ-receptor antagonist ICI 174,864. Lett Pept Sci. 1994;1:107–115. doi: 10.1007/BF00128528. [DOI] [Google Scholar]
  • 19.Flippen-Anderson JL, Hruby VJ, Collins N, George C, Cudney B. X-ray structure of [D-Pen2, D-Pen5]enkephalin, a highly potent, delta-opioid receptor-selective compound: comparisons with proposed solution conformations. J Am Chem Soc. 1994;116:7523–7531. doi: 10.1021/ja00096a008. [DOI] [Google Scholar]
  • 20.Collins N, Flippen-Anderson JL, Haaseth R, et al. Conformational determinants of agonist versus antagonist properties of [D-Pen2, D-Pen5]-enkephalin (DPDPE) analogs at opioid receptors: comparison of x-ray crystallographic structure, solution1H NMR data, and molecular dynamic simulations of [L-Ala3]DPDPE and [D-Ala3]DPDPE. J Am Chem Soc. 1996;118:2143–2152. doi: 10.1021/ja9531081. [DOI] [Google Scholar]
  • 21.Nikiforovich GV, Kover KE, Kolodziej SA, et al. Design and comprehensive conformational studies of Tyr1-cyclo(D-Pen2-Gly3-Phe5-l-3-Mpt5) and Tyr(1)-cyclo(Pen2-Gly3-Phe5-d-3-Mpt5): novel conformationally constrained opioid peptides. J Am Chem Soc. 1996;118:959–969. doi: 10.1021/ja952964+. [DOI] [Google Scholar]
  • 22.Lomize AL, Flippen-Anderson JL, George C, Mosberg HI. Conformational-analysis of the delta-receptor-selective, cyclic opioid peptide, Tyr-cyclo[D-Cys-Phe-D-Pen]OH (JOM-13): comparison of X-ray crystallographic structures, molecular mechanics simulation, and1H-NMR data. J Am Chem Soc. 1994;116:429–436. doi: 10.1021/ja00081a001. [DOI] [Google Scholar]
  • 23.Flippen-Anderson JL, Deschamps JR, George C, et al. X-ray structure of Tyr-D-Tic-Phe-Phe-NH2 (D-TIPP-NH2), a highly potent μ-receptor selective opioid agonist: comparisons with proposed model structures. J Pept Res. 1997;49:384–393. doi: 10.1111/j.1399-3011.1997.tb00890.x. [DOI] [PubMed] [Google Scholar]
  • 24.Ciajolo MR, Balboni G, Picone D, et al. A solution and solid-state structure of the diketopiperazine of tyrosyl-tetrahydroisoquinoline-3-carboxylic acid. Int J Pept Protein Res. 1995;46:134–138. doi: 10.1111/j.1399-3011.1995.tb01328.x. [DOI] [PubMed] [Google Scholar]
  • 25.Deschamps JR, Flippen-Anderson JL, George C. 2-[N-(t-Butoxy carbonyl)tyrosyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid nitromethane solvate. Acta Crystallogr. 2001;57E:o87–o90. [Google Scholar]
  • 26.Deschamps JR, Flippen-Anderson JL, Moore C, Cudney R, George C. Tyrosyl-D-tetrahydroisoquinoline-3-carboxylic acid and tyrosyl-D-tetrahydroisoquinoline-3-carboxamide. Acta Crystallogr. 1997;C53:1478–1482. doi: 10.1107/s0108270197006975. [DOI] [PubMed] [Google Scholar]
  • 27.Bryant SD, George C, Flippen-Anderson JL, et al. Crystal structures of dipeptides containing the DMT-TIC pharmacophore. J Med Chem. 2002;45:5506–5513. doi: 10.1021/jm020330p. [DOI] [PubMed] [Google Scholar]
  • 28.Petsko GA. On the other hand…. Science. 1992;256:1403–1404. doi: 10.1126/science.1604313. [DOI] [PubMed] [Google Scholar]
  • 29.Milton RC, Milton SCF, Kent BBH. Total chemical synthesis of a D-enzyme: the enantiomers of HIV-1 protease show demonstration of reciprocal chiral substrate specificity. Science. 1992;256:1445–1448. doi: 10.1126/science.1604320. [DOI] [PubMed] [Google Scholar]
  • 30.Coster D, Knol KS, Prins JA. Unterschiede in der intensität der röntgenstrahlen-feflexion an den beiden 111-flächen der zinkblende. Z Phys. 1930;63:345–369. doi: 10.1007/BF01339610. [DOI] [Google Scholar]
  • 31.Bijvoet JM, Peerdeman AF, van Bommel AJ. Determination of the absolute configuration of optically active compounds by means of X-rays. Nature. 1951;168:271–272. doi: 10.1038/168271a0. [DOI] [Google Scholar]
  • 32.Flack HD. On enantiomorph-polarity estimation. Acta Crystallogr. 1983;A39:876–881. [Google Scholar]
  • 33.Schiller PW, Nguyen TMD, Weltrowska G, et al. Differential stereochemical requirments of μ vs δ opioid receptors for ligand binding and signal transduction: development of a class of potent and highly δ-selective peptide antagonists. Proc Natl Acad Sci USA. 1992;89:11871–11875. doi: 10.1073/pnas.89.24.11871. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Balboni G, Guerrini R, Salvadori S, et al. Evaluation of the Dmt-Tic pharmacophore: conversion of a potent delta-opioid receptor antagonist into a potent delta agonist and ligands with mixed properties. J Med Chem. 2002;45:713–720. doi: 10.1021/jm010449i. [DOI] [PubMed] [Google Scholar]
  • 35.Eddy NB, May EL. The search for a better analgesic. Science. 1973;181:407–414. doi: 10.1126/science.181.4098.407. [DOI] [PubMed] [Google Scholar]
  • 36.Schiller PW, Yam CF, Lis M. Evidence of topographical analogy between methionine-enkephalin and morphine derivatives. Biochemistry. 1977;16:1831–1838. doi: 10.1021/bi00628a011. [DOI] [PubMed] [Google Scholar]
  • 37.Gylbert L. The crystal and molecule structure of morphine hydrochloride trihydrate. Acta Crystallogr. 1973;B29:1630–1635. [Google Scholar]
  • 38.Thomas G. Medicinal Chemistry: An Introduction. Chichester, UK: John Wiley & Sons; 2000. [Google Scholar]
  • 39.Foye WO, Lemke TL, Williams DA. Principles of Medicinal Chemistry. Baltimore, MD: Williams & Wilkins; 1995. [Google Scholar]
  • 40.Michel AG, Evrard G, Norberg B, Milchert E. Molecular-Structure of Opiate Alkaloids. 2. Crystal-Structures of 4-Methylhomobenzomorphan Hydrobromide (I) and 4,12-beta-Dimethylhomobenzomorphan (II) Can J Chem. 1988;66:1763–1769. doi: 10.1139/v88-284. [DOI] [Google Scholar]
  • 41.Thomas JB, Zheng XL, Mascarella SW, et al. N-substituted 9β-methyl-5-(3-hyroxyphenyl)morphans are opioid receptor pure antagonists. J Med Chem. 1998;41:4143–4149. doi: 10.1021/jm980290i. [DOI] [PubMed] [Google Scholar]
  • 42.Hashimoto A, Jabobson AE, Rothman RB, et al. Probes for narcotic receptor mediated phenomena. 28. New opioid antagonists from enantiomeric analogues ofm-hydroxyphenyl-N-phenylethylmorphan. Bioorg Med Chem. 2002;10:3319–3329. doi: 10.1016/S0968-0896(02)00219-5. [DOI] [PubMed] [Google Scholar]
  • 43.Flippen-Anderson JL, George C, Bertha CM, Rice KC. X-ray crystal structures of potent opioid receptor ligands: etonitazene,cis-(+)-3-methylfentanyl, etorphine, diprenorphine, and buprenorphine. Heterocycles. 1994;39:751–766. doi: 10.3987/COM-94-S(B)70. [DOI] [Google Scholar]
  • 44.Hruby VJ, Gehrig CA. Recent developments in the design of receptor specifico-peptides. Med Res Rev. 1989;9:343–401. doi: 10.1002/med.2610090306. [DOI] [PubMed] [Google Scholar]

Articles from The AAPS Journal are provided here courtesy of American Association of Pharmaceutical Scientists

RESOURCES