Structural genomics: Bridging functional genomics and structure-based drug design

Current Opinion in Drug Discovery and Development

Volumn 5, Issue 3, 2002, Pages 367-381

  Buchanan, Sean G ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

Drug selectivity; Fold recognition; Gene annotation; Genomics; Homology modeling; Pharmacogenomics; Structure prediction; Structure based drug design; Virtual screening

Indexed keywords

ANTIBIOTIC AGENT; ANTIRETROVIRUS AGENT; BACTERIAL ENZYME; BACTERIAL PROTEIN; CASPASE; MEVALONIC ACID; PRALNACASAN; PROTEIN KINASE; PROTEINASE INHIBITOR; PX 740;

DATA BASE; DRUG BINDING SITE; DRUG DESIGN; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG TARGETING; GENOMICS; HELICOBACTER PYLORI; HUMAN IMMUNODEFICIENCY VIRUS 1; METHANOCOCCUS JANNASCHII; MODEL; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PHARMACOGENOMICS; PROTEIN STRUCTURE; REVIEW; THERMOTOGA MARITIMA; VIBRIO; X RAY CRYSTALLOGRAPHY;

DRUG DESIGN; GENOMICS; HUMANS; PROTEIN CONFORMATION; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0036589881     PISSN: 13676733     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (184)

1. Burley SK: An overview of structural genomics. Nat Struct Biol (2000) 7:932-934.
2. Waldo GS, Standish BM, Berendzen J, Terwilliger TC: Rapid protein-folding assay using green fluorescent protein. Nat Biotechnol (1999) 17:691-695.
3. Edwards AM, Arrowsmith CH, Christendat D, Dharamsi A, Friesen JD, Greenblatt JF, Vedadi M: Protein production:-Feeding the crystallographers and NMR spectroscopists. Nat Struct Biol (2000) 7:970-972.
4. Abola E, Kuhn P, Earnest T, Stevens RC: Automation of X-ray crystallography. Nat Struct Biol (2000) 7:973-977.
5. Stevens RC: High-throughput protein crystallization. Curr Opin Struct Biol (2000) 10:558-563.
6. Rayment I: Small-scale batch crystallization of proteins revisited. An underutilized way to grow large protein crystals. Structure (2002) 10:147-151.
7. Mueller U, Nyarsik L, Horn M, Rauth H, Przewieslik T, Saenger W, Lehrach H, Eickhoff H: Development of a technology for automation and miniaturization of protein crystallization. J Biotechnol (2001) 85:7-14.
8. Muchmore SW, Olson J, Jones R, Pan J, Blum M, Greer J, Merrick SM, Magdalinos P, Nienaber VL: Automated crystal mounting and data collection for protein crystallography. Structure Fold Des (2000) 8:R243-R246.
9. Hendrickson WA: Synchrotron crystallography. Trends Biochem Sci (2000) 25:637-643.
10. Dauter Z, Dauter M, de La Fortelle E, Bricogne G, Sheldrick GM: Can anomalous signal of sulfur become a tool for solving protein crystal structures? J Mol Biol (1999) 289:83-92.
11. Kissinger CR, Gehlhaar DK, Smith BA, Bouzida D: Molecular replacement by evolutionary search. Acta Crystallogr D Biol Crystallogr (2001) 57:1474-1479.
12. Lamzin VS, Perrakis A: Current state of automated crystallographic data analysis. Nat Struct Biol (2000) 7:978-981.
13. Weiss MS, Sicker T, Hilgenfeld R: Soft X-rays, high redundancy, and proper scaling: A new procedure for automated protein structure determination via SAS. Structure (2001) 9:771-777.
14. Prestegard JH, Valafar H, Glushka J, Tian F: Nuclear magnetic resonance in the era of structural genomics. Biochemistry (2001) 40:8677-8685.
15. Head-Gordon T, Wooley JC: Computational challenges in structural and functional genomics. IBM Systems J (2001) 40:265-296.
16. Skolnick J, Fetrow JS, Kolinski A: Structural genomics and its importance for gene function analysis. Nat Biotechnol (2000) 18:283-287.
17. Teichmann SA, Chothia C, Gerstein M: Advances in structural genomics. Curr Opin Struct Biol (1999) 9:390-399.
18. Thomton JM, Todd AE, Milburn D, Borkakoti N, Orengo CA: From structure to function: Approaches and limitations. Nat Struct Biol (2000) 7:991-994.
19. Ostermeier C, Michel H: Crystallization of membrane proteins. Curr Opin Struct Biol (1997) 7:697-701.
20. Landau EM, Rosenbusch JP: Lipidic cubic phases: A novel concept for the crystallization of membrane proteins. Proc Natl Acad Sci USA (1996) 93:14532-14535.
21. Stewart L, Clark R, Behnke C: High-throughput crystallization and structure determination in drug discovery. Drug Disc Today (2002) 7:187-196.
22. Vitkup D, Melamud E, Moult J, Sander C: Completeness in structural genomics. Nat Struct Biol (2001) 8:559-566.
23. Harris T: Genetics, genomics, and drug discovery. Med Res Rev (2000) 20:203-211.
24. Dry S, McCarthy S, Harris T: Structural genomics in the biotechnology sector. Nat Struct Biol (2000) 7:946-949.
25. Blundell TL, Jhoti H, Abell C: High-throughput crystallography for lead discovery in drug design. Nat Rev Drug Dis (2002) 1:45-54. An excellent overview covering the evolution of crystallography to the current state-of-art technologies and methodologies in high- throughput structure determination and lead discovery.
26. Buchanan SG, Sauder JM, Harris T: The promise of structural genomics in the discovery of new antimicrobial agents. Curr Pharm Des (2002) 8: in press. A review that complements this one, covering the role of structural genomics in antimicrobial drug discovery.
27. Meyers TC, Turano TA, Greenhalgh DA, Waller PR: Patent protection for protein structures and databases. Nat Struct Biol (2000) 7:950-952.
28. Murzin AG: How far divergent evolution goes in proteins. Curr Opin Struct Biol (1998) 8:380-387.
29. L, an inhibitor of programmed cell death. Nature (1996) 381:335-341.
30. Fesik SW: Insights into programmed cell death through structural biology. Cell (2000) 103:273-282.
31. Bennett MS, Guan Z, Laurberg M, Su X-D: Bacillus subtilis arsenate reductase is structurally and functionally similar to low molecular weight protein tyrosine phosphatases. Proc Natl Acad Sci USA (2001) 98:13577-13582. This paper describes the unexpected homology between arsenate reductase and mammalian low molecular weight tyrosine phosphatases. The detection of this relationship relied on structural similarity and leads to a proposal for the enzymatic mechanism.
32. Zegers I, Martins JC, Willem R, Wyns L, Messens J: Arsenate reductase from S. aureus plasmid p1258 is a phosphatase drafted for redox duty. Nat Struct Biol (2001) 8:843-847. The structure of arsenate reductase (ArsC) from Staphylococcus aureus resembles the Bacillus subtilis structure [31·], and similar conclusions were drawn. In both studies, the authors show that ArsC displays tyrosine phosphatase as well as arsenate reductase activity. Interestingly, the Escherichia coli arsenate reductase belongs to a different structural class.
33. Koppensteiner WA, Lackner P, Wiederstein M, Sippl MJ: Characterization of novel proteins based on known protein structures. J Mol Biol (2000) 296:1139-1152.
34. Jones DT, Tress M, Bryson K, Hadley C: Successful recognition of protein folds using threading methods biased by sequence similarity and predicted secondary structure. Proteins (1999) 37:S104-S111.
35. Jin S, Martinek S, Joo WS, Wortman JR, Mirkovic N, Sali A, Yandell MD, Pavletich NP, Young MW, Levine AJ: Identification and characterization of a p53 homologue in Drosophila melanogaster. Proc Natl Acad Sci USA (2000) 97:7301-7306.
36. Schaffer AA, Wolf YI, Ponting CP, Koonin EV, Aravind L, Altschul SF: IMPALA: Matching a protein sequence against a collection of PSI-BLAST-constructed position-specific score matrices. Bioinformatics (1999) 15:1000-1011.
37. Al-Lazikani B, Sheinerman FB, Honig B: Combining multiple structure and sequence alignments to improve sequence detection and alignment: Application to the SH2 domains of Janus kinases. Proc Natl Acad Sci USA (2001) 98:14796-14801. Using sophisticated sequence profile and structure alignment methods, this group demonstrates the possibility of extending the reach of conventional homology detection using sequence methods.
38. Sauder JM, Arthur JW, Dunbrack RL: Large-scale comparison of protein sequence alignment algorithms with structure alignments. Proteins (2000) 40:6-22.
39. Bolten E, Schliep A, Schneckener S, Schomburg D, Schrader R: Clustering protein sequences - structure prediction by transitive homology. Bioinformatics (2001) 17:935-941.
40. Wallqvist A, Fukunishi Y, Murphy LR, Fadel A, Levy RM: Iterative sequence/secondary structure search for protein homologs: Comparison with amino acid sequence alignments and application to fold recognition in genome databases. Bioinformatics (2000) 16:988-1002.
41. Pegg SC, Babbitt PC: Shotgun: Getting more from sequence similarity searches. Bioinformatics (1999) 15:729-740.
42. Lappe M, Park J, Niggemann O, Holm L: Generating protein interaction maps from incomplete data: Application to fold assignment. Bioinformatics (2001) 17:S149-S156.
43. Baker D: A surprising simplicity to protein folding. Nature (2000) 405:39-42. This commentary summarizes some of the latest developments in the fields of protein folding and ab initio structure prediction.
44. Pillardy J, Czaplewski C, Liwo A, Lee J, Ripoll DR, Kázmierkiewicz R, Oldziej S, Wedemeyer WJ, Gibson KD, Amautova YA, Saunders J, Ye Y-J, Scheraga HA: Recent improvements in prediction of protein structure by global optimization of a potential energy function. Proc Natl Acad Sci USA (2001) 98:2329-2333.
45. Simons KT, Strauss C, Baker D: Prospects for ab initio protein structural genomics. J Mol Biol (2001) 306:1191-1199.
46. Lazaridis T, Karplus M: Effective energy functions for protein structure prediction. Curr Opin Struct Biol (2000) 10:139-145.
47. Sippl MJ, Lackner P, Domingues FS, Prlic A, Malik R, Andreeva A, Wiederstein M: Assessment of the CASP4 fold recognition category. Proteins (2001) 45:S55-S67.
48. Lesk AM, Lo Conte L, Hubbard TJ: Assessment of novel fold targets in CASP4: Predictions of three-dimensional structures, secondary structures, and interresidue contacts. Proteins (2001) 45:S98-S118.
49. Bonneau R, Strauss CEM, Baker D: Improving the performance of rosetta using multiple sequence alignment information and global measures of hydrophobic core formation. Proteins (2001) 43:1-11. The top ranking group at CASP4 describes improvements to Rosetta.
50. Zhou ZH, Baker ML, Jiang W, Dougherty M, Jakana J, Dong G, Lu G, Chiu W: Electron cryomicroscopy and bioinformatics suggest protein fold models for rice dwarf virus. Nat Struct Biol (2001) 8:868-873.
51. Wallace BA, Janes RW: Synchrotron radiation circular dichroism spectroscopy of proteins: Secondary structure, fold recognition and structural genomics. Curr Opin Chem Biol (2001) 5:567-571.
52. Young MM, Tang N, Hempel JC, Oshiro CM, Taylor EW, Kuntz ID, Gibson BW, Dollinger G: High-throughput protein fold identification by using experimental constraints derived from intramolecular cross-links and mass spectrometry. Proc Natl Acad Sci USA (2000) 97:5802-5806.
53. Bowers PM, Strauss CE, Baker D: De novo protein structure determination using sparse NMR data. J Biomol NMR (2000) 18:311-318.
54. Sanchez R, Pieper U, Melo F, Eswar N, Marti-Renom MA, Madhusudhan MS, Mirkovic N, Sali A: Protein structure modeling for structural genomics. Nat Struct Biol (2000) 7:S986-S990.
55. Pieper U, Eswar N, Stuart AC, Ilyin VA, Sali A: MODBASE, a database of annotated comparative protein structure models. Nucleic Acids Res (2002) 30:255-259.
56. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W et al: Initial sequencing and analysis of the human genome. Nature (2001) 409:860-921.
57. Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, Yandell M, Evans CA, Holt RA et al. The sequence of the human genome. Science (2001) 291:1304-1351.
58. Murray D, Honig B: Electrostatic control of the membrane targeting of C2 domains. Mol Cell (2002) 9:145-154. This paper demonstrates how analysis of the electrostatic potential within a protein family can lead to functional revelations and predictions. The C2 domain is a phospholipid binding module that functions to target proteins to membrane compartments. Different lipid compositions characterize different compartments and are recognized by the differing electrostatic features of C2 domains.
59. Christendat D, Yee A, Dharamsi A, Kluger Y, Savchenko A, Cort JR, Booth V, Mackereth CD, Saridakis V, Ekiel I, Kozlov G, Maxwell KL, Wu N, McIntosh LP, Gehring K, Kennedy MA, Davidson AR, Pai EF, Gerstein M, Edwards AM, Arrowsmith CH: Structural proteomics of an archaeon. Nat Struct Biol (2000) 7:903-909.
60. Eisenstein E, Gilliland GL, Herzberg O, Moult J, Orban J, Poljak RJ, Banerjei L, Richardson D, Howard AJ: Biological function made crystal clear - annotation of hypothetical proteins via structural genomics. Curr Opin Biotechnol (2000) 11:25-30.
61. Marcotte EM, Pellegdni M, Thompson MJ, Yeates TO, Eisenberg D: A combined algorithm for genome-wide prediction of protein function. Nature (1999) 402:83-86.
62. Lay AJ, Jiang XM, Kisker O, Flynn E, Underwood A, Condron R, Hogg PJ: Phosphoglycerate kinase acts in tumour angiogenesis as a disulphide reductase. Nature (2000) 408:869-873.
63. Todd AE, Orengo CA, Thomton JM: Evolution of function in protein superfamilies, from a structural perspective. J Mol Biol (2001) 307:1113-1143. A comprehensive analysis of the relationship between structure, function and sequence conservation. The authors analyzed the distribution of Enzyme Commission (EC) numbers within CATH superfamilies. They derive statistics describing the functional variation within homologous groups and analyze, in depth, certain enzyme and structural families to uncover the evolutionary processes underlying these findings.
64. Orengo CA, Michie AD, Jones S, Jones DT, Swindells MB, Thomton JM: CATH - a hierarchic classification of protein domain structures. Structure (1997) 5:1093-1108.
65. Shapiro L, Harris T: Finding function through structural genomics. Curr Opin Biotechnol (2000) 11:31-35.
66. Kim SH: Shining a light on structural genomics. Nat Struct Biol (1998) 5:S643-S645.
67. Zarembinski TI, Hung L-W, Mueller-Dieckmann H-J, Kim K-K, Yokota H, Kim R, Kim S-H: Structure-based assignment of the biochemical function of a hypothetical protein: A test case of structural genomics. Proc Natl Acad Sci USA (1998) 95:15189-15193.
68. Aloy P, Querol E, Aviles FX, Stemberg MJ: Automated structure-based prediction of functional sites in proteins: Applications to assessing the validity of inheriting protein function from homology in genome annotation and to protein docking. J Mol Biol (2001) 311:395-408.
69. Parsons JF, Lim K, Tempczyk A, Krajewski W, Eisenstein E, Herzberg O: From structure to function: Yrbl from Haemophilus influenzae (HI1679) is a phosphatase. Proteins (2002) 46:393-404. Yrbl adopts the Rossmann fold, an architecture conscripted to a number of different enzymatic functions. However, further analysis of the sequence and structure indicated a connection with phosphoserine phosphatase, and phosphatase activity was subsequently demonstrated.
70. Holm L, Sander C: The FSSP database: Fold classification based on structure-structure alignment of proteins. Nucleic Acids Res (1996) 24:206-209.
71. Murzin AG, Brenner SE, Hubbard T, Chothia C: SCOP: A structural classification of proteins database for the investigation of sequences and structures. J Mol Biol (1995) 247:536-540.
72. Dietmann S, Holm L: Identification of homology in protein structure classification. Nat Struct Biol (2001) 8:953-957.
73. Pearl FM, Martin N, Bray JE, Buchan DW, Harrison AP, Lee D, Reeves GA, Shepherd AJ, Sillitoe I, Todd AE, Thomton JM, Orengo CA: A rapid classification protocol for the CATH Domain Database to support structural genomics. Nucleic Acids Res (2001) 29:223-227.
74. Lo Conte L, Brenner SE, Hubbard TJ, Chothia C, Murzin AG: SCOP database in 2002: Refinements accommodate structural genomics. Nucleic Acids Res (2002) 30:264-267.
75. Martinez-Cruz LA, Dreyer MK, Boisvert DC, Yokota H, Martinez-Chantar ML, Kim R, Kim SH: Crystal structure of MJ1247 protein from M. jannaschii at 2.0 Å resolution infers a molecular function of 3-hexulose-6-phosphate Isomerase. Structure (2002) 10:195-204.
76. Laskowski RA, Luscombe NM, Swindells MB, Thomton JM: Protein clefts in molecular recognition and function. Protein Sci (1996) 5:2438-2452.
77. Brady GP Jr, Stouten PF: Fast prediction and visualization of protein binding pockets with PASS. J Comput Aided Mol Des (2000) 14:383-401.
78. Ruppert J, Welch W, Jain AN: Automatic identification and representation of protein binding sites for molecular docking. Protein Sci (1997) 6:524-533.
79. Madabushi S, Yao H, Marsh M, Kristensen DM, Philippi A, Sowa ME, Lichtarge O: Structural clusters of evolutionary trace residues are statistically significant and common in proteins. J Mol Biol (2002) 316:139-164.
80. Lichtarge O, Boume HR, Cohen FE: An evolutionary trace method defines binding surfaces common to protein families. J Mol Biol (1996) 257:342-358.
81. Sowa ME, He W, Slep KC, Kercher MA, Lichtarge O, Wensel TG: Prediction and confirmation of a site critical for effector regulation of RGS domain activity. Nat Struct Biol (2001) 8:234-237.
82. Stawiski EW, Baucom AE, Lohr SC, Gregoret LM: Predicting protein function from structure: Unique structural features of proteases. Proc Natl Acad Sci USA (2000) 97:3954-3958.
83. Ondrechen MJ, Clifton JG, Ringe D: THEMATICS: A simple computational predictor of enzyme function from structure. Proc Natl Acad Sci USA (2001) 98:12473-12478.
84. Wallace AC, Laskowski RA, Thornton JM: Derivation of 3D coordinate templates for searching structural databases: Application to Ser-His-Asp catalytic triads in the serine proteinases and lipases. Protein Sci (1996) 5:1001-1013.
85. Wallace AC, Borkakoti N, Thomton JM: TESS: A geometric hashing algorithm for deriving 3D coordinate templates for searching structural databases. Application to enzyme active sites. Protein Sci (1997) 6:2308-2323.
86. Fetrow JS, Skolnick J: Method for prediction of protein function from sequence using the sequence-to-structure- to-function paradigm with application to glutaredoxins/thioredoxins and T1 ribonucleases. J Mol Biol (1998) 281:949-968.
87. Singh PK, Schaefer AL, Parsek MR, Moninger TO, Welsh MJ, Greenberg EP: Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature (2000) 407:762-764.
88. Sperandio V, Mellies JL, Nguyen W, Shin S, Kaper JB: Quorum sensing controls expression of the type III secretion gene transcription and protein secretion in enterohemorrhagic and enteropathogenic Escherichia coli. Proc Natl Acad Sci USA (1999) 96:15196-15201.
89. Zhu J, Miller MB, Vance RE, Dziejman M, Bassler BL, Mekalanos JJ: Quorum-sensing regulators control virulence gene expression in Vibrio cholerae. Proc Natl Acad Sci USA (2002) 99:3129-3134.
90. Smith RS, Harris SG, Phipps R, Iglewski B: The Pseudomonas aeruginosa quorum-sensing molecule N-(3- oxododecanoyl)homoserine lactone contributes to virulence and induces inflammation in vivo. J Bacteriol (2002) 184:1132-1139.
91. Bassler BL: How bacteria talk to each other: Regulation of gene expression by quorum sensing. Curr Opin Microbiol (1999) 2:582-587.
92. Lewis HA, Furlong EB, Laubert B, Eroshkina GA, Batiyenko Y, Adams JM, Bergseid MG, Marsh CD, Peat TS, Sanderson WE, Sauder JM, Buchanan SG: A structural genomics approach to the study of quorum sensing: Crystal structures of three LuxS orthologs. Structure (2001) 9:527-537. The structure of LuxS from three different organisms led to a hypothesis of both the function and mechanism of this protein. The experiments show that LuxS is a zinc metalloenzyme remotely related to a domain of threonyl tRNA synthetase.
93. Chen X, Schauder S, Potier N, Van Dorsselaer A, Pelczer I, Bassler BL, Hughson FM: Structural identification of a bacterial quorum-sensing signal containing boron. Nature (2002) 415:545-549. LuxP from Vibrio harveyi structurally resembles periplasmic binding proteins. Density in the region of LuxP corresponding to the canonical binding site of this class of receptors led to the identification of Al-2 as a furanosly borate diester.
94. Zhang RG, Skarina T, Katz JE, Beasley S, Khachatryan A, Vyas S, Arrowsmith CH, Clarke S, Edwards A, Joachimiak A, Savchenko A: Structure of Thermotoga maritima stationary phase survival protein SurE: A novel acid phosphatase. Structure (2001) 9:1095-1106.
95. Lee JY, Kwak JE, Moon J, Eom SH, Liong EC, Pedelacq JD, Berendzen J, Suh SW: Crystal structure and functional analysis of the SurE protein identify a novel phosphatase family. Nat Struct Biol (2001) 8:789-794.
96. Pawlowski K, Godzik A: Surface map comparison: Studying function diversity of homologous proteins. J Mol Biol (2001) 309:793-806.
97. Boggon TJ, Shan WS, Santagata S, Myers SC, Shapiro L: Implication of tubby proteins as transcription factors by structure-based functional analysis. Science (1999) 286:2119-2125.
98. Teplova M, Tereshko V, Sanishvili R, Joachimiak A, Bushueva T, Anderson WF, Egli M: The structure of the yrdC gene product from Escherichia coli reveals a new fold and suggests a role in RNA binding. Protein Sci (2000) 9:2557-2566.
99. Bonanno JB, Edo C, Eswar N, Pieper U, Romanowski MJ, Ilyin V, Gerchman SE, Kycia H, Studier FW, Sali A, Burley SK: Structural genomics of enzymes involved in sterol/isoprenoid biosynthesis. Proc Natl Acad Sci USA (2001) 98:12896-12901. This study illustrates the manner in which solving a carefully chosen selection of targets, combined with automated homology modeling technology, can rapidly provide comprehensive structural coverage of a pathway and within a family. In this case, two structures have been leveraged into 379 additional models from the mevalonate IPP pathway and the GHMP kinase family.
100. Greer J, Erickson JW, Baldwin JJ, Vamey MD: Application of the three-dimensional structures of protein target molecules in structure-based drug design. J Med Chem (1994) 37:1035-1054.
101. von Itzstein M, Wu WY, Kok GB, Pegg MS, Dyason JC, Jin B, Van Phan T, Smythe ML, White HF, Oliver SW et al. Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature (1993) 363:418-423.
102. Bayly Cl, Black WC, Leger S, Ouimet N, Ouellet M, Percival MD: Structure-based design of COX-2 selectivity into flurbiprofen. Bioorg Med Chem Lett (1999) 9:307-312.
103. Schindler T, Bommann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J: Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science (2000) 289:1938-1942.
104. Bohm HJ, Stahl M: Structure-based library design: Molecular modelling merges with combinatorial chemistry. Curr Opin Chem Biol (2000) 4:283-286.
105. Lamb ML, Burdick KW, Toba S, Young MM, Skillman AG, Zou X, Amold JR, Kuntz ID: Design, docking, and evaluation of multiple libraries against multiple targets. Proteins (2001) 42:296-318.
106. Cheng M, De B, Pikul S, Almstead NG, Natchus MG, Anastasio MV, McPhail SJ, Snider CE, Taiwo YO, Chen L, Dunaway CM, Gu F, Dowty ME, Mieling GE, Janusz MJ, Wang-Weigand S: Design and synthesis of piperazine-based matrix metalloproteinase inhibitors. J Med Chem (2000) 43:369-380.
107. Mihelich ED, Schevitz RW: Structure-based design of a new class of anti-inflammatory drugs: Secretory phospholipase A(2) inhibitors, SPI. Biochim Biophys Acta (1999) 1441:223-228.
108. Matthews DA, Dragovich PS, Webber SE, Fuhrman SA, Patick AK, Zalman LS, Hendrickson TF, Love RA, Prins TJ, Marakovits JT, Zhou R, Tikhe J, Ford CE, Meador JW, Ferre RA, Brown EL, Binford SL, Brothers MA, DeLisle DM, Worland ST: 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 (1999) 96:11000-11007.
109. Liu KG, Lambert MH, Ayscue AH, Henke BR, Leesnitzer LM, Oliver WR Jr, Plunket KD, Xu HE, Sternbach DD, Willson TM: Synthesis and biological activity of L-tyrosine-based PPARγ agonists with reduced molecular weight. Bioorg Med Chem Lett (2001) 11:3111-3113.
110. Carter AP, Clemons WM, Brodersen DE, Morgan-Warren RJ, Wimberly BT, Ramakrishnan V: Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics. Nature (2000) 407:340-348.
111. Schlünzen F, Zarivach R, Harms J, Bashan A, Tocilj A, Albrecht R, Yonath A, Franceschi F: Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature (2001) 413:814-821. Determination of the structure of the ribosome is one of the major achievements in molecular biology It will also be of considerable interest to antibacterial drug discovery groups since resistance to translation inhibitors has evolved through mutations in ribosome components (see [112]).
112. Pioletti M, Schlunzen F, Harms J, Zarivach R, Gluhmann M, Avila H, Bashan A, Bartels H, Auerbach T, Jacobi C, Hartsch T, Yonath A, Franceschi F: Crystal structures of complexes of the small ribosomal subunit with tetracycline, edeine and IF3. EMBO J (2001) 20:1829-1839. Determination of the structure of the ribosome is one of the major achievements in molecular biology. It will also be of considerable interest to antibacterial drug discovery groups since resistance to translation inhibitors has evolved through mutations in ribosome components (see [111··]).
113. Brodersen DE, Clemons WM Jr, Carter AP, Morgan-Warren RJ, Wimbedy BT, Ramakrishnan V: The structural basis for the action of the antibiotics tetracycline, pactamycin, and hygromycin B on the 30S ribosomal subunit. Cell (2000) 103:1143-1154.
114. Parang K, Till JH, Ablooglu AJ, Kohanski RA, Hubbard SR, Cole PA: Mechanism-based design of a protein kinase inhibitor. Nat Struct Biol (2001) 8:37-41.
115. Iversen LF, Andersen HS, Møller KB, Olsen OH, Peters GH, Branner S, Mortensen SB, Hansen TK, Lau J, Ge Y, Holsworth DD, Newman MJ, Hundahl-Møller NP: Steric hindrance as a basis for structure-based design of selective inhibitors of protein-tyrosine phosphatases. Biochemistry (2001) 40:14812-14820.
116. Cronet P, Petersen JF, Folmer R, Blomberg N, Sjoblom K, Karlsson U, Lindstedt EL, Bamberg K: Structure of the PPARα and -γ ligand binding domain in complex with AZ 242; ligand selectivity and agonist activation in the PPAR family. Structure (2001) 9:699-706.
117. Xu HE, Lambert MH, Montana VG, Plunket KD, Moore LB, Collins JL, Oplinger JA, Kliewer SA, Gampe RT Jr, McKee DD, Moore JT, Willson TM: Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA (2001) 98:13919-13924.
118. Myszka DG, Rich RL: Implementing surface plasmon resonance biosensors in drug discovery. Pharm Sci Technol Today (2000) 3:310-317.
119. Hajduk PJ, Bures M, Praestgaard J, Fesik SW: Privileged molecules for protein binding identified from NMR-based screening. J Med Chem (2000) 43:3443-3447.
120. Feizo J, Lepre CA, Peng JW, Bemis GW, Ajay, Murcko MA, Moore JM: The SHAPES strategy: An NMR-based approach for lead generation in drug discovery. Chem Biol (1999) 6:755-769.
121. Dennis MS, Eigenbrot C, Skelton NJ, Ultsch MH, Santell L, Dwyer MA, O'Connell MP, Lazarus RA: Peptide exosite inhibitors of factor Vila as anticoagulants. Nature (2000) 404:465-470.
122. Shuker SB, Hajduk PJ, Meadows RP, Fesik SW: Discovering high-affinity ligands for proteins: SAR by NMR. Science (1996) 274:1531-1534.
123. Nienaber VL, Richardson PL, Klighofer V, Bouska JJ, Giranda VL, Greer J: Discovering novel ligands for macromolecules using X-ray crystallographic screening. Nat Biotechnol (2000) 18:1105-1108.
124. Ganesan A: Recent developments in combinatorial organic synthesis. Drug Disc Today (2002) 7:47-55.
125. Ding S, Gray NS, Wu X, Ding Q, Schultz PG: A combinatorial scaffold approach toward kinase-directed heterocycle libraries. J Am Chem Soc (2002) 124:1594-1596.
126. Ramström O, Lehn J-M: Drug discovery by dynamic combinatorial libraries. Nat Rev Drug Dis (2002) 1:26-36.
127. Stout TJ, Sage CR, Stroud RM: The additivity of substrate fragments in enzyme-ligand binding. Structure (1998) 6:839-848.
128. Erlanson DA, Braisted AC, Raphael DR, Randal M, Stroud RM, Gordon EM, Wells JA: Site-directed ligand discovery. Proc Natl Acad Sci USA (2000) 97:9367-9372.
129. Hann MM, Leach AR, Harper G: Molecular complexity and its impact on the probability of finding leads for drug discovery. J Chem Inf Comput Sci (2001) 41:856-864.
130. Ringe D, Mattos C: Analysis of the binding surfaces of proteins. Med Res Rev (1999) 19:321-331.
131. Tondi D, Powers RA, Caselli E, Negri MC, Blazquez J, Costi MP, Shoichet BK: Structure-based design and in-parallel synthesis of inhibitors of AmpC β-lactamase. Chem Biol (2001) 8:593-611.
132. Laskowski RA, Thomton JM, Humblet C, Singh J: X-SITE: Use of empirically derived atomic packing preferences to identify favourable interaction regions in the binding sites of proteins. J Mol Biol (1996) 259:175-201.
133. Gohlke H, Hendlich M, Klebe G: Knowledge-based scoring function to predict protein-ligand interactions. J Mol Biol (2000) 295:337-356.
134. Frye SV: Structure-activity relationship homology (SARAH): A conceptual framework for drug discovery in the genomic era. Chem Biol (1999) 6:R3-R7.
135. Denessiouk KA, Rantanen V-V, Johnson MS: Adenine recognition: A motif present in ATP-, CoA-, NAD-, NADP-, and FAD-dependent proteins. Proteins (2001) 44:282-291.
136. Denesyuk AI, Denessiouk KA, Korpela T, Johnson MS: Functional attributes of the phosphate group binding cup of pyridoxal phosphate-dependent enzymes. J Mol Biol (2002) 316:155-172.
137. Fairlie DP, Tyndall JDA, Reid RC, Wong AK, Abbenante G, Scanlon MJ, March DR, Bergman DA, Chai CLL, Burkett BA: Conformational selection of inhibitors and substrates by proteolytic enzymes: Implications for drug design and polypeptide processing. J Med Chem (2000) 43:1271-1281.
138. Kastenholz MA, Pastor M, Cruciani G, Haaksma EEJ, Fox T: GRID/CPCA: A new computational tool to design selective ligands. J Med Chem (2000) 43:3033-3044.
139. Wei Y, Fox T, Chambers SP, Sintchak J, Coll JT, Golec JM, Swenson L, Wilson KP, Charifson PS: The structures of caspases-1, -3, -7 and -8 reveal the basis for substrate and inhibitor selectivity. Chem Biol (2000) 7:423-432.
140. Hanks SK, Hunter T: Protein kinases 6. The eukaryotic protein kinase superfamily: Kinase (catalytic) domain structure and classification. FASEB J (1995) 9:576-596.
141. Dwight SS, Harris MA, Dolinski K, Ball CA, Binkley G, Christie KR, Fisk DG, Issel-Tarver L, Schroeder M, Sherlock G, Sethuraman A, Weng S, Botstein D, Cherry JM: Saccharomyces Genome Database (SGD) provides secondary gene annotation using the Gene Ontology (GO). Nucleic Acids Res (2002) 30:69-72.
142. Ogata H, Goto S, Sato K, Fujibuchi W, Bono H, Kanehisa M: KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res (1999) 27:29-34.
143. Stuart AC, Ilyin VA, Sali A: LigBase: A database of families of aligned ligand binding sites in known protein sequences and structures. Bioinformatics (2002) 18:200-201.
144. Hendlich M: Databases for protein-ligand complexes. Acta Crystallogr D Biol Crystallogr (1998) 54:1178-1182.
145. Freire E: Designing drugs against heterogeneous targets. Nat Biotechnol (2002) 20:15-16.
146. von Bubnoff N, Schneller F, Peschel C, Duyster J: BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: A prospective study. Lancet (2002) 359:487-491.
147. Rohdich F, Kis K, Bacher A, Eisenreich W: The non- mevalonate pathway of isoprenoids: Genes, enzymes and intermediates. Curr Opin Chern Biol (2001) 5:535-540.
148. Richard SB, Bowman ME, Kwiatkowski W, Kang I, Chow C, Lillo AM, Cane DE, Noel JP: Structure of 4- diphosphocytidyl-2-C-methylerythritol synthetase involved in mevalonate-independent isoprenoid biosynthesis. Nat Struct Biol (2001) 8:641-648.
149. Richard SB, Ferrer JL, Bowman ME, Lillo AM, Tetzlaff CN, Cane DE, Noel JP: Structure and Mechanism of 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase. An enzyme in the mevalonate independent isoprenoid biosynthetic pathway. J Biol Chem (2002) 277:8667-8672.
150. Steinbacher S, Kaiser J, Wungsintaweekul J, Hecht S, Eisenreich W, Gerhardt S, Bacher A, Rohdich F: Structure of 2 C-m ethyl-D-erythritol-2,4-cyclodiphosphate synthase involved in mevalonate-independent biosynthesis of isoprenoids. J Mol Biol (2002) 316:79-88.
151. Reuter K, Sanderbrand S, Jomaa H, Wiesner J, Steinbrecher I, Beck E, Hintz M, Klebe G, Stubbs MT: Crystal structure of 1- deoxy-D-xylulose-5-phosphate reductoisomerase, a crucial enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. J Biol Chem (2002) 277:5378-5384.
152. Born TL, Blanchard JS: Structure/function studies on enzymes in the diaminopimelate pathway of bacterial cell wall biosynthesis. Curr Opin Chem Biol (1999) 3:607-613.
153. Erlandsen H, Abola EE, Stevens RC: Combining structural genomics and enzymology: Completing the picture in metabolic pathways and enzyme active sites. Curr Opin Struct Biol (2000) 10:719-730.
154. Good A: Structure-based virtual screening protocols. Curr Opin Drug Discovery Dev (2001) 4:301-307.
155. Abagyan R, Totrov M: High-throughput docking for lead generation. Curr Opin Chem Biol (2001) 5:375-382.
156. Schneider G, Bohm HJ: Virtual screening and fast automated docking methods. Drug Disc Today (2002) 7:64-70.
157. Schapira M, Raaka BM, Samuels HH, Abagyan R: Rational discovery of novel nuclear hormone receptor antagonists. Proc Natl Acad Sci USA (2000) 97:1008-1013.
158. Perola E, Xu K, Kollmeyer TM, Kaufmann SH, Prendergast FG, Pang Y-P: Successful virtual screening of a chemical database for farnesyltransferase inhibitor leads. J Med Chem (2000) 43:401-408.
159. Enyedy IJ, Ling Y, Nacro K, Tomita Y, Wu X, Cao Y, Guo R, Li B, Zhu X, Huang Y, Long YQ, Roller PP, Yang D, Wang S: Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening. J Med Chem (2001) 44:4313-4324.
160. Ridderström M, Zamora I, Fjellström O, Andersson TB: Analysis of selective regions in the active sites of human cytochromes P450, 2C8, 2C9, 2C18, and 2C19 homology models using GRID/CPCA. J Med Chem (2001) 44:4072-4081.
161. Schafferhans A, Klebe G: Docking ligands onto binding site representations derived from proteins built by homology modelling. J Mol Biol (2001) 307:407-427.
162. Diller DJ, Merz KM Jr: High-throughput docking for library design and library prioritization. Proteins (2001) 43:113-124.
163. Maggio ET, Ramnarayan K: Recent developments in computational proteomics. Drug Disc Today (2001) 6:996-1004.
164. Good AC, Krystek SR, Mason JS: High-throughput and virtual screening: Core lead discovery technologies move towards integration. Drug Disc Today (2000) 5:S61-S69.
165. Engels MF, Venkatarangan P: Smart screening: Approaches to efficient HTS. Curr Opin Drug Discovery Dev (2001) 4:275-283.
166. Carlson HA, McCammon JA: Accommodating protein flexibility in computational drug design. Mol Pharmacol (2000) 57:213-218.
167. Jones G, Willett P, Glen RC, Leach AR, Taylor R: Development and validation of a genetic algorithm for flexible docking. J Mol Biol (1997) 267:727-748.
168. Schnecke V, Kuhn LA: Database screening for HIV protease ligands: The influence of binding-site conformation and representation on ligand
169. Broughton HB: A method for including protein flexibility in protein-ligand docking: Improving tools for database mining and virtual screening. J Mol Graph Model (2000) 18:247-257.
170. Ota N, Agard DA: Binding mode prediction for a flexible ligand in a flexible pocket using multi-conformation simulated annealing pseudo crystallographic refinement. J Mol Biol (2001) 314:607-617.
171. Kollman PA, Massova I, Reyes C, Kuhn B, Huo S, Chong L, Lee M, Lee T, Duan Y, Wang W, Donini O, Cieplak P, Srinivasan J, Case DA, Cheatham TE III: Calculating structures and free energies of complex molecules: Combining molecular mechanics and continuum models. Acc Chem Res (2000) 33:889-897.
172. Stahl M, Rarey M: Detailed analysis of scoring functions for virtual screening. J Med Chem (2001) 44:1035-1042.
173. Bissantz C, Folkers G, Rognan D: Protein-based virtual screening of chemical databases. 1. Evaluation of different docking/scoring combinations. J Med Chem (2000) 43:4759-4767.
174. Chen YZ, Zhi DG: Ligand-protein inverse docking and its potential use in the computer search of protein targets of a small molecule. Proteins (2001) 43:217-226.
175. Mitchell T, Showell GA: Design strategies for building drug-like chemical libraries. Curr Opin Drug Discovery Dev (2001) 4:314-318.
176. Williams PA, Cosme J, Sridhar V, Johnson EF, McRee DE: Mammalian microsomal cytochrome P450 monooxygenase: Structural adaptations for membrane binding and functional diversity. Mol Cell (2000) 5:121-131.
177. Watkins RE, Wisely GB, Moore LB, Collins JL, Lambert MH, Williams SP, Willson TM, Kliewer SA, Redinbo MR: The human nuclear xenobiotic receptor PXR: Structural determinants of directed promiscuity. Science (2001) 292:2329-2333.
178. Roden DM, George AL Jr: The genetic basis of variability in drug responses. Nat Rev Drug Dis (2002) 1:37-44.
179. Wang Z, Moult J: SNPs, protein structure, and disease. Hum Mutat (2001) 17:263-270. The cataloging of the common SNPs in database such as dbSNP provides a wealth of information pertinent to drug discovery. A substantial fraction of these SNPs affect protein coding regions and their effects can be predicted by mapping them to protein structure models. This study, along with those reported in references [182] and [183], begins to analyze the effects of such non-synonymous SNPs and leads to conclusions about the fraction of SNPs that map to ligand binding sites.
180. Fukami H, Okunishi H, Miyazaki M: Chymase: Its pathophysiological roles and inhibitors. Curr Pharm Des (1998) 4:439-453.
181. McGrath ME, Mirzadegan T, Schmidt BF: Crystal structure of phenylmethanesulfonyl fluoride-treated human chymase at 1.9 A. Biochemistry (1997) 36:14318-14324.
182. Sunyaev S, Ramensky V, Bork P: Towards a structural basis of human non-synonymous single nucleotide polymorphisms. Trends Genet (2000) 16:198-200.
183. Chasman D, Adams RM: Predicting the functional consequences of non-synonymous single nucleotide polymorphisms: Structure-based assessment of amino acid variation. J Mol Biol (2001) 307:683-706.
184. Adam D: Database of molecular probes set to boost chemical genetics. Nature (2001) 411:873.