Abstract
The majority of drugs available today were discovered either by chance observations or by screening synthetic or natural products libraries. In many cases, a trialand-error based approach of chemical modification of lead compounds led to an improvement with respect to potency and reduced toxicity. Since this approach is labor and time-intense, researchers in the pharmaceutical industry are constantly developing methods to increase the efficiency of the drug finding process. Simply put, two directions have evolved from these efforts. The “random” approach involves the development of high-throughput screening assays and the testing of a large number of compounds. Combinatorial chemistry is used to satisfy the need for huge substance libraries. The “rational,” structure-based approach relies on an iterative procedure of structure determination of the target protein, prediction of hypothetical ligands by molecular modeling, specific chemical synthesis and biological testing of compounds (the structure-based drug design cycle). It is becoming evident, that the future of drug discovery does not lie in one of these approaches solely, but rather an intelligent combination. In this chapter, we will concentrate on the protein structure-based drug discovery approach and discuss possible overlaps with complementary technologies.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Zimmerle CT, Alter GM (1983) Crystallization-induced modification of cytoplasmic malate dehydrogenase structure and function. Biochemistry 22: 6273–6281
Tanenbaum DM, Wang Y, Williams SP et al (1998) Crystallographic comparison of the estrogen and progesterone receptor’s ligand binding domains. Proc Natl Acad Sci USA 95: 5998–6003
Lu J, Lin CL, Tang C et al (1999) The structure and dynamics of rat apo-cellular retinol-binding protein II in solution: comparison with the X-ray structure. J Mol Biol 286: 1179–1195
Billeter M, Kline AD, Braun W et al (1989) Comparison of the high-resolution structures of the alpha-amylase inhibitor tendamistat determined by nuclear magnetic resonance in solution and by X-ray diffraction in single crystals. J Mol Biol 206: 677–687
Billeter M (1992) Comparison of protein structures determined by NMR in solution and by X-ray diffraction in single crystals. Q Rev Biophys 25: 325–377
Wuthrich K (1989) Determination of three-dimensional protein structures in solution by nuclear magnetic resonance: an overview. Methods Enzymol 177: 125–131
McIntosh LP, Dahlquist FW (1990) Biosynthetic incorporation of 15N and 13C for assignment and interpretation of nuclear magnetic resonance spectra of proteins. Q Rev Biophys 23: 1–38
Karplus M (1963) Vicinal proton coupling in nuclear magnetic resonance. J Am Chem Soc 85: 2870–2871
Kuntz ID, Thomason JF, Oshiro CM (1989) Distance geometry. Methods Enzymol 177: 159–204
Scheek RM, van GW, Kaptein R (1989) Molecular dynamics simulation techniques for determination of molecular structures from nuclear magnetic resonance data. Methods Enzymol 177: 204–218
Brunger AT (1997) X-ray crystallography and NMR reveal complementary views of structure and dynamics. Nat Struct Biol 4 Suppl: 862–865
Pervushin K, Riek R, Wider G et al (1997) Attenuated T2 relaxation by mutual cancellation of dipole-dipole coupling and chemical shift anisotropy indicates an avenue to NMR structures of very large biological macromolecules in solution. Proc Natl Acad Sci USA 94: 12366–12371
Riek R, Wider G, Pervushin K et al (1999) Polarization transfer by cross-correlated relaxation in solution NMR with very large molecules. Proc Natl Acad Sci USA 96: 4918–4923
Riek R, Pervushin K, Wuthrich K (2000) TROSY and CRINEPT: NMR with large molecular and supramolecular structures in solution. Trends Biochem Sci 25: 462–468
Lesk AM, Chothia CH (1986) The response of protein structures to amino-acid sequence changes. Philos Trans R Soc London Ser B 317: 345–356
Altschul SF, Gish W, Miller W et al (1990) Basic local alignment search tool. J Mol Biol 215: 403–410
Pearson WR, Lipman DJ (1988) Improved tools for biological sequence comparison. Proc Natl Acad Sci USA 85: 2444–2448
Zheng Q, Kyle DJ (1996) Accuracy and reliability of the scaling-relaxation method for loop closure: an evaluation based on extensive and multiple copy conformational samplings. Proteins 24: 209–217
Rapp CS, Friesner RA (1999) Prediction of loop geometries using a generalized born model of solvation effects. Proteins 35: 173–183
Fiser A, Do RK, Sali A (2000) Modeling of loops in protein structures. Protein Sci 9: 1753–1773
Jones TA, Thirup S (1986) Using known substructures in protein model building and crystallography. EMBO J 5: 819–822
Claessens M, Van Cutsem E, Lasters I et al (1989) Modelling the polypeptide backbone with ‘spare parts’ from known protein structures. Protein Eng 2: 335–345
Li W, Liu Z, Lai L (1999) Protein loops on structurally similar scaffolds: database and conformational analysis. Biopolymers 49: 481–495
Wojcik J, Mornon JP, Chomilier J (1999) New efficient statistical sequence-dependent structure prediction of short to medium-sized protein loops based on an exhaustive loop classification. J Mol Biol 289: 1469–1490
Vasquez M (1996) Modeling side-chain conformation. Curr Opin Struct Biol 6: 217–221
Dunbrack RLJ, Karplus M (1994) Conformational analysis of the backbone-dependent rotamer preferences of protein sidechains. Nat Struct Biol 1: 334–340
Bower MJ, Cohen FE, Dunbrack RLJ (1997) Prediction of protein side-chain rotamers from a backbone-dependent rotamer library: a new homology modeling tool. J Mol Biol 267: 1268–1282
Dunbrack RLJ (1999) Comparative modeling of CASP3 targets using PSI-BLAST and SCWRL. Proteins Suppl 3: 81–87
De Maeyer M, Desmet J, Lasters I (1997) All in one: a highly detailed rotamer library improves both accuracy and speed in the modelling of sidechains by dead-end elimination. Fold Des 2: 53–66
Cheng B, Nayeem A, Scheraga HA (1996) From secondary structure to three-dimensional structure: Improved dihedral angle probability distribution function for use with energy searches for native structures of polypeptides and proteins. J Comp Chem 17: 1453–1480
Shenkin PS, Farid H, Fetrow JS (1996) Prediction and evaluation of side-chain conformations for protein backbone structures. Proteins 26: 323–352
Lovell SC, Word JM, Richardson JS et al (2000) The penultimate rotamer library. Proteins 40: 389–408
Laskowski RA, MacArthur MW, Moss DS et al (1993) PROCHECK: a program to check the stereo-chemical quality of protein structures. J Appl Cryst 26: 283–291
Hooft RW, Vriend G, Sander C et al (1996) Errors in protein structures. Nature 381: 272
EU 3-D Validation Network (1998) Who checks the checkers? Four validation tools applied to eight atomic resolution structures. J Mol Biol 276: 417–436
Murzin AG, Brenner SE, Hubbard T et al (1995) SCOP: a structural classification of proteins database for the investigation of sequences and structures. J Mol Biol 247: 536–540
Hendlich M (1998) Databases for protein-ligand complexes. Acta Crystallogr D Biol Crystallogr 54: 1178–1182
Laskowski RA (2001) PDBsum: summaries and analyses of PDB structures. Nucleic Acids Res 29: 221–222
Vondrasek J, van Buskirk CP, Wlodawer A (1997) Database of three-dimensional structures of HIV proteinases. Nat Struct Biol 4: 8
Sanchez R, Pieper U, Mirkovic N et al (2000) MODBASE, a database of annotated comparative protein structure models. Nucleic Acids Res 28: 250–253
Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234: 779–815
Peitsch MC, Schwede T, Guex N (2000) Automated protein modelling—the proteome in 3D. Pharmacogenomics 1: 257–266
Edwards AM, Arrowsmith CH, Christendat D et al (2000) Protein production: feeding the crystallographers and NMR spectroscopists. Nat Struct Biol 7 Suppl: 970–972
Abola E, Kuhn P, Earnest T et al (2000) Automation of x-ray crystallography. Nat Struct Biol 7 Suppl: 973–977
Lamzin VS, Perrakis A (2000) Current state of automated crystallographic data analysis. Not Struct Biol 7 Suppl: 978–981
Montelione GT, Zheng D, Huang YJ et al (2000) Protein NMR spectroscopy in structural genomics. Nat Struct Biol 7 Suppl: 982–985
Burley SK (2000) An overview of structural genomics. Nat Struct Biol 7 Suppl: 932–934
Service RF (2000) Structural genomics offers high-speed look at proteins. Science 287: 1954–1956
Brenner SE (2000) Target selection for structural genomics. Nat Struct Biol 7 Suppl: 967–969
Marti-Renom MA, Stuart AC, Fiser A et al (2000) Comparative protein structure modeling of genes and genomes. Annu Rev Biophys Biomol Struct 29: 291–325
Schafferhans A, Klebe G (2001) Docking Ligands onto Binding Site Representations Derived from Proteins built by Homology Modelling. J Mol Biol 307: 407–427
Schapira M, Raaka BM, Samuels HH et al (2000) Rational discovery of novel nuclear hormone receptor antagonists. Proc Nati Acad Sci USA 97: 1008–1013
Spencer TA, Li D, Russel JS et al (2001) Pharmacophore analysis of the nuclear oxysterol receptor LXRalpha. J Med Chem 44: 886–897
Cushman DW, Cheung HS, Sabo EF et al (1977) Design of potent competitive inhibitors of angiotensin-converting enzyme. Carboxyalkanoyl and mercaptoalkanoyl amino acids. Biochemistry 16: 5484–5491
Lipscomb WN, Reeke GNJ, Hartsuck JA et al (1970) The structure of carboxypeptidase A. 8. Atomic interpretation at 0.2 nm resolution, a new study of the complex of glycyl-L-tyrosine with CPA, and mechanistic deductions. Philos Trans R Soc Lond B Biol Sci 257: 177–214
Petrillo EWJ, Ondetti MA (1982) Angiotensin-converting enzyme inhibitors: medicinal chemistry and biological actions. Med Res Rev 2: 1–41
Goodman LS, Gilman A (1996) Goodman & Gilman’s The pharmakological basis of therapeutics. McGraw-Hill, New York
Eriksson AE, Jones TA, Liljas A (1988) Refined structure of human carbonic anhydrase II at 2.0 A resolution. Proteins 4: 274–282
Greer J, Erickson JW, Baldwin JJ et al (1994) Application of the three-dimensional structures of protein target molecules in structure-based drug design. J Med Chem 37: 1035–1054
Wlodawer A, Miller M, Jaskolski M et al (1989) Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease. Science 245: 616–621
Thaisrivongs S, Strohbach JW (1999) Structure-based discovery of Tipranavir disodium (PNU140690E): a potent, orally bioavailable, nonpeptidic HIV protease inhibitor. Biopolymers 51: 51–58
Palese P, Schulman JL, Bodo G et al (1974) Inhibition of influenza and parainfluenza virus replication in tissue culture by 2-deoxy-2,3-dehydro-N-trifluoroacetylneuraminic acid (FANA). Virology 59: 490–498
Varghese JN, Laver WG, Colman PM (1983) Structure of the influenza virus glycoprotein antigen neuraminidase at 2.9 A resolution. Nature 303: 35–40
von Itzstein M, Wu WY, Kok GB et al (1993) Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 363: 418–423
Kim CU, Lew W, Williams MA et al (1997) Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: Design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J Am Chem Soc 119: 681–690
Mascaretti OA, Danelon GO, Laborde M et al (1999) Recent advances in the chemistry of beta-lactam compounds as selected active-site serine beta-lactamase inhibitors. Curr Pharm Des 5: 939–953
Heinze-Krauss I, Angehrn P, Charnas RL et al (1998) Structure-based design of beta-lactamase inhibitors. 1. Synthesis and evaluation of bridged monobactams. J Med Chem 41: 3961–3971
Kryger G, Silman I, Sussman JL (1999) Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs. Structure Fold Des 7: 297–307
Wilson DK, Petrash JM, Quiocho FA (1997) Structural studies of aldose reductase inhibition. In: Structure-based drug design, edited by P. Veerapandian, pp. 229–246. Marcel Dekker, Inc., New York, Basel, Hong Kong
Iwata Y, Arisawa M, Hamada R et al (2001) Discovery of novel aldose reductase inhibitors using a protein structure-based approach: 3D-database search followed by design and synthesis. J Med Chem 44: 1718–1728
Ondetti MA, Rubin B, Cushman DW (1977) Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. Science 196: 441–444
Bohacek RS, McMartin C, Guida WC (1996) The art and practice of structure-based drug design: a molecular modeling perspective. Med Res Rev 16: 3–50
Vidgren J (1998) X-ray crystallography of catechol 0-methyltransferase: perspectives for target-based drug development. Adv Pharmacol 42: 328–331
Masjost B, Ballmer P, Borroni E et al (2000) Structure-based design, synthesis, and in vitro evaluation of bisubstrate inhibitors for catechol 0-methyltransferase (COMT). Chemistry 6: 971–982
Katunuma N, Murata E, Kakegawa H et al (1999) Structure based development of novel specific inhibitors for cathepsin L and cathepsin S in vitro and in vivo. FEBS Lett 458: 6–10
Katunuma N, Matsui A, Inubushi T et al (2000) Structure-based development of pyridoxal propionate derivatives as specific inhibitors of cathepsin K in vitro and in vivo. Biochem Biophys Res Commun 267: 850–854
Bayly CI, Black WC, Leger S et al (1999) Structure-based design of COX-2 selectivity into flurbiprofen. Bioorg Med Chem Lett 9: 307–312
Szklarz GD, Halpert JR (1998) Molecular basis of P450 inhibition and activation: implications for drug development and drug therapy. Drug Metab Dispos 26: 1179–1184
Gschwend DA, Sirawaraporn W, Santi DV et al (1997) Specificity in structure-based drug design: identification of a novel, selective inhibitor of Pneumocystis carinii dihydrofolate reductase. Proteins 29: 59–67
Zuccotto F, Brun R, Gonzalez PD et al (1999) The structure-based design and synthesis of selective inhibitors of Trypanosoma cruzi dihydrofolate reductase. Bioorg Med Chem Lett 9: 1463–1468
Rosowsky A, Cody V, Galitsky N et al (1999) Structure-based design of selective inhibitors of dihydrofolate reductase: synthesis and antiparasitic activity of 2, 4-diaminopteridine analogues with a bridged diarylamine side chain. J Med Chem 42: 4853–4860
Cregge RI, Durham SL, Farr RA et al (1998) Inhibition of human neutrophil elastase. 4. Design, synthesis, X-ray crystallographic analysis, and structure-activity relationships for a series of P2-modified, orally active peptidyl pentafluoroethyl ketones. J Med Chem 41: 2461–2480
Filippusson H, Erlendsson LS, Lowe CR (2000) Design, synthesis and evaluation of biomimetic affinity ligands for elastases. J Mol Recognit 13: 370–381
Tedesco R, Thomas JA, Katzenellenbogen BS et al (2001) The estrogen receptor: a structure-based approach to the design of new specific hormone-receptor combinations. Chem Biol 8: 277–287
Stauffer SR, Coletta CJ, Tedesco R et al (2000) Pyrazole ligands: structure-affinity/activity relationships and estrogen receptor-alpha-selective agonists. J Med Chem 43: 4934–4947
Phillips G, Davey DD, Eagen KA et al (1999) Design, synthesis, and activity of 2,6-diphenoxypyridine-derived factor Xa inhibitors. J Med Chem 42: 1749–1756
Arnaiz DO, Zhao Z, Liang A et al (2000) Design, synthesis, and in vitro biological activity of indolebased factor Xa inhibitors. Bioorg Med Chem Lett 10: 957–961
Han Q, Dominguez C, Stouten PF et al (2000) Design, synthesis, and biological evaluation of potent and selective amidino bicyclic factor Xa inhibitors. J Med Chem 43: 4398–4415
Kaminski JJ, Rane DF, Snow ME et al (1997) Identification of novel farnesyl protein transferase inhibitors using three-dimensional database searching methods. J Med Chem 40: 4103–4112
Navia MA (1996) Protein-drug complexes important for immunoregulation and organ transplantation. Curr Opin Struct Biol 6: 838–847
Burkhard P, Hommel U, Sanner M et al (1999) The discovery of steroids and other novel FKBP inhibitors using a molecular docking program. J Mot Biol 287: 853–858
van Neuren AS, Muller G, Klebe G et al (1999) Molecular modelling studies on G protein-coupled receptors: from sequence to structure? J Recept Signal Transduct Res 19: 341–353
Muller G (2000) Towards 3D structures of G protein-coupled receptors: a multidisciplinary approach. Curr Med Chem 7: 861–888
Martin F, Dimasi N, Volpari C et al (1998) Design of selective eglin inhibitors of HCV NS3 proteinase. Biochemistry 37: 11459–11468
Debnath AK, Radigan L, Jiang S (1999) Structure-based identification of small molecule antiviral compounds targeted to the gp41 core structure of the human immunodeficiency virus type 1. J Med Chem 42: 3203–3209
Hong H, Neamati N, Wang S et al (1997) Discovery of HIV-1 integrase inhibitors by pharmacophore searching. J Med Chem 40: 930–936
Wlodawer A, Vondrasek J (1998) Inhibitors of HIV-1 protease: a major success of structure-assisted drug design. Annu Rev Biophys Biomol Struct 27: 249–284
De Lucca GV, Erickson-Viitanen S, Lam PY (1997) Cyclic HIV protease inhibitors capable of displacing the active site structural water molecule. Drug Discov Today 2: 6–18
Arnold E, Das K, Ding Jet al (1996) Targeting HIV reverse transcriptase for anti-AIDS drug design: structural and biological considerations for chemotherapeutic strategies. Drug Des Discov 13: 29–47
Mao C, Sudbeck EA, Venkatachalam TK et al (2000) Structure-based drug design of non-nucleoside inhibitors for wild-type and drug-resistant HIV reverse transcriptase. Biochem Pharmacol 60: 1251–1265
Wade RC (1997) ‘Flu’ and structure-based drug design. Structure 5: 1139–1145
Shahripour AB, Plummer MS, Lunney EA et al (2002) Structure-based design of nonpeptide inhibitors of interleukin-lbeta converting enzyme (ICE, caspase-1). Bioorg Med Chem 10: 31–40
Zask A, Levin JI, Killar LM et al (1996) Inhibition of matrix metalloproteinases: structure based design. Curr Pharm Des 2: 624–661
Brown PD (1998) Matrix metalloproteinase inhibitors. Breast Cancer Res Treat 52: 125–136
Matter H, Schwab W, Barbier D et al (1999) Quantitative structure-activity relationship of human neutrophil collagenase (MMP-8) inhibitors using comparative molecular field analysis and X-ray structure analysis. J Med Chem 42: 1908–1920
Cheng M, De B, Pikul S et al (2000) Design and synthesis of piperazine-based matrix metalloproteinase inhibitors. J Med Chem 43: 369–380
Huang H, Martasek P, Roman LJ et al (2000) Synthesis and evaluation of peptidomimetics as selective inhibitors and active site probes of nitric oxide synthases. J Med Chem 43: 2938–2945
Oliver WRJ, Shenk JL, Snaith MR et al (2001) A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci USA 98: 5306–5311
Schevitz RW, Bach NJ, Carlson DG et al (1995) Structure-based design of the first potent and selec-tive inhibitor of human non-pancreatic secretory phospholipase A2. Nat Struct Biol 2: 458–465
Mihelich ED, Schevitz RW (1999) Structure-based design of a new class of anti-inflammatory drugs: secretory phospholipase A(2) inhibitors, SPI. Biochim Biophys Acta 1441: 223–228
Bursi R, Groen MB (2000) Application of (quantitative) structure-activity relationships to progestagens: from serendipity to structure-based design. Eur J Med Chem 35: 787–796
al-Obeidi FA, Wu JJ, Lam KS (1998) Protein tyrosine kinases: structure, substrate specificity, and drug discovery. Biopolymers 47: 197–223
Shakespeare W, Yang M, Bohacek R et al (2000) Structure-based design of an osteoclast-selective, nonpeptide src homology 2 inhibitor with in vivo antiresorptive activity. Proc Natl Acad Sci USA 97: 9373–9378
Toledo LM, Lydon NB, Elbaum D (1999) The structure-based design of ATP-site directed protein kinase inhibitors. Curr Med Chem 6: 775–805
Sudbeck EA, Liu XP, Narla RK et al (1999) Structure-based design of specific inhibitors of Janus kinase 3 as apoptosis-inducing antileukemic agents. Clin Cancer Res 5: 1569–1582
Furet P, Garcia-Echeverria C, Gay B et al (1999) Structure-based design, synthesis, and X-ray crystallography of a high-affinity antagonist of the Grb2-SH2 domain containing an asparagine mimetic. J Med Chem 42: 2358–2363
Burke TRJ, Zhang ZY (1998) Protein-tyrosine phosphatases: structure, mechanism, and inhibitor discovery. Biopolymers 47: 225–241
Doman TN, McGovern SL, Witherbee BJ et al (2002) Molecular docking and high-throughput screening for novel inhibitors of protein tyrosine phosphatase-1B. J Med Chem 45: 2213–2221
Yao ZJ, Ye B, Wu XW et al (1998) Structure-based design and synthesis of small molecule protein-tyrosine phosphatase 1B inhibitors. Bioorg Med Chem 6: 1799–1810
Iversen LF, Andersen HS, Branner S et al (2000) Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selective inhibitor of protein-tyrosine phosphatase 1B. J Biol Chem 275: 10300–10307
Ealick SE, Babu YS, Bugg CE et al (1991) Application of crystallographic and modeling methods in the design of purine nucleoside phosphorylase inhibitors. Proc Natl Acad Sci USA 88: 11540–11544
Montgomery JA (1994) Structure-based drug design: inhibitors of purine nucleoside phosphorylase. Drug Des Discov 11: 289–305
Dhanaraj V, Cooper JB (1997)Rational design of renin inhibitors. In: Structure-based drug design, edited by P. Veerapandian, pp. 321–342. Marcel Dekker, Inc., New York, Basel, Hong Kong
Hutchins C, Greer J (1991) Comparative modeling of proteins in the design of novel renin inhibitors. Crit Rev Biochem Mol Biol 26: 77–127
Rahuel J, Rasetti V, Maibaum J et al (2000) Structure-based drug design: the discovery of novel non-peptide orally active inhibitors of human renin. Chem Biol 7: 493–504
Nagpal S, Chandraratna RA (2000) Recent developments in receptor-selective retinoids. Curr Pharm Des 6: 919–931
Giranda VL (1994) Structure-based drug design of antirhinoviral compounds. Structure 2: 695–698
Matthews DA, Dragovich PS, Webber SE et al (1999) Structure-assisted design of mechanism-based irreversible inhibitors of human rhinovirus 3C protease with potent antiviral activity against multiple rhinovirus serotypes. Proc Natl Acad Sci USA 96: 11000–11007
Reich SH, Johnson T, Wallace MB et al (2000) Substituted benzamide inhibitors of human rhinovirus 3C protease: structure-based design, synthesis, and biological evaluation. J Med Chem 43: 1670–1683
Read M, Harrison RJ, Romagnoli B et al (2001) Structure-based design of selective and potent G quadruplex-mediated telomerase inhibitors. Proc Natl Acad Sci USA 98: 4844–4849
Sanderson PE, Naylor-Olsen AM (1998) Thrombin inhibitor design. Curr Med Chem 5: 289–304
Stubbs MT, Bode W (1993) A player of many parts: the spotlight falls on thrombin’s structure. Thromb Res 69: 1–58
Costi MP (1998) Thymidylate synthase inhibition: a structure-based rationale for drug design. Med Res Rev 18: 21–42
Greenidge PA, Carlsson B, Bladh LG et al (1998) Pharmacophores incorporating numerous excluded volumes defined by X-ray crystallographic structure in three-dimensional database searching: application to the thyroid hormone receptor. J Med Chem 41: 2503–2512
Callens M, Hannaert V (1995) The rational design of trypanocidal drugs: selective inhibition of the glyceraldehyde-3-phosphate dehydrogenase in Trypanosomatidae. Ann Trop Med Parasitol 89 Suppl 1: 23–30
Aronov AM, Suresh S, Buckner FS et al (1999) Structure-based design of submicromolar, biologically active inhibitors of trypanosomatid glyceraldehyde-3-phosphate dehydrogenase. Proc Natl Acad Sci USA 96: 4273–4278
Uckun FM, Mao C, Vassilev AO et al (2000) Structure-based design of a novel synthetic spiroketal pyran as a pharmacophore for the marine natural product spongistatin 1. Bioorg Med Chem Lett 10: 541–545
Zeslawska E, Schweinitz A, Karcher A et al (2000) Crystals of the urokinase type plasminogen activator variant beta(c)-uPAin complex with small molecule inhibitors open the way towards structure-based drug design. J Mol Biol 301: 465–475
Nienaber VL, Davidson D, Edalji R et al (2000) Structure-directed discovery of potent non-peptidic inhibitors of human urokinase that access a novel binding subsite. Structure Fold Des 8: 553–563
Ring CS, Sun E, McKerrow JH et al (1993) Structure-based inhibitor design by using protein models for the development of antiparasitic agents. Proc Natl Acad Sci USA 90: 3583–3587
Li Z, Chen X, Davidson E et al (1994) Anti-malarial drug development using models of enzyme structure. Chem Biol 1: 31–37
Garforth J, Yin H, McKie JH et al (1997) Rational design of selective ligands for trypanothione reductase from Trypanosoma cruzi. Structural effects on the inhibition by dibenzazepines based on imipramine. J Enzyme Inhib 12: 161–173
McKie JH, Douglas KT, Chan C et al (1998) Rational drug design approach for overcoming drug resistance: application to pyrimethamine resistance in malaria. J Med Chem 41: 1367–1370
Folkers G, Alber F, Amrhein I et al (1997) Integrated homology modelling and X-ray study of herpes simplex virus I thymidine kinase: a case study. J Recept Signal Transduct Res 17: 475–494
Traxler P, Furet P, Mett H et al (1997) Design and synthesis of novel tyrosine kinase inhibitors using a pharmacophore model of the ATP-binding site of the EGF-R. J Pharm Belg 52: 88–96
Mahajan S, Ghosh S, Sudbeck EA et al (1999) Rational design and synthesis of a novel anti-leukemic agent targeting Bruton’s tyrosine kinase (BTK), LFM-A13 [alpha-cyano-beta-hydroxy-betamethyl-N-(2, 5-dibromophenyl)propenamide]. J Biol Chem 274: 9587–9599
Gussio R, Zaharevitz DW, McGrath CF et al (2000) Structure-based design modifications of the paullone molecular scaffold for cyclin-dependent kinase inhibition. Anticancer Drug Des 15: 53–66
Sabb AL, Husbands GM, Tokolics J et al (1999) Discovery of a highly potent, functionally-selective muscarinic M1 agonist, WAY-132983 using rational drug design and receptor modelling. Bioorg Med Chem Lett 9: 1895–1900
Marhefka CA, Moore BM, Bishop TC et al (2001) Homology modeling using multiple molecular dynamics simulations and docking studies of the human androgen receptor ligand binding domain bound to testosterone and nonsteroidal ligands. J Med Chem 44: 1729–1740
Thornton JM, Todd AE, Milburn D et al (2000) From structure to function: approaches and limitations. Nat Struct Biol 7 Suppl: 991–994
Zarembinski TI, Hung LW, Mueller-Dieckmann HJ et al (1998) Structure-based assignment of the biochemical function of a hypothetical protein: a test case of structural genomics. Proc Natl Acad Sci USA 95: 15189–15193
Kleywegt GJ (1999) Recognition of spatial motifs in protein structures. J Mol Biol 285: 1887–1897
Xu LZ, Sanchez R, Sali A et al (1996) Ligand specificity of brain lipid-binding protein. J Biol Chem 271: 24711–24719
Lewis DF (2000) Modelling human cytochromes P450 for evaluating drug metabolism: an update. Drug Metabol Drug Interact 16: 307–324
Doyle DA, Morais CJ, Pfuetzner RA et al (1998) The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280: 69–77
Armstrong N, Sun Y, Chen GQ et al (1998) Structure of a glutamate-receptor ligand-binding core in complex with kainate. Nature 395: 913–917
Brejc K, van Dijk WJ, Klaassen RV et al (2001) Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411: 269–276
Palczewski K, Kumasaka T, Hori T et al (2000) Crystal structure of rhodopsin: A G protein-coupled receptor. Science 289: 739–745
Istvan ES, Deisenhofer J (2001) Structural mechanism for stat n inhibition of HMG-CoA reductase. Science 292: 1160–1164
Ban N, Nissen P, Hansen J et al (2000) The complete atomic structure of the large ribosomal subunit at 2.4 A resolution. Science 289: 905–920
Berchtold H, Hilgenfeld R (1999) Binding of phenol to R6 insulin hexamers. Biopolymers 51: 165–172
Ohlenschlager O, Ramachandran R, Giihrs KH et al (1998) Nuclear magnetic resonance solution structure of the plasminogen-activator protein staphylokinase. Biochemistry 37: 10635–10642
Steinmetzer K, Hillisch A, Behlke J et al (2000) Transcriptional repressor CopR: structure model-based localization of the deoxyribonucleic acid binding motif. Proteins 38: 393–406
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2003 Springer Basel AG
About this chapter
Cite this chapter
Hillisch, A., Hilgenfeld, R. (2003). The role of protein 3D-structures in the drug discovery process. In: Hillisch, A., Hilgenfeld, R. (eds) Modern Methods of Drug Discovery. EXS, vol 93. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-7997-2_8
Download citation
DOI: https://doi.org/10.1007/978-3-0348-7997-2_8
Publisher Name: Birkhäuser, Basel
Print ISBN: 978-3-0348-9397-8
Online ISBN: 978-3-0348-7997-2
eBook Packages: Springer Book Archive