Conotoxin therapeutics: A pipeline for success?

Expert Opinion on Drug Discovery

Volumn 2, Issue 4, 2007, Pages 453-468

  Grant, Marianne A ^a   Shanmugasundaram, Kumaran ^a   Rigby, Alan C ^a,b  

^a Center for Vascular Biology Research   (United States)

^b MOUNT DESERT ISLAND BIOLOGICAL LABORATORY   (United States)

Author keywords

Computer aided drug discovery; Peptide therapeutics; Pharmacophore

Indexed keywords

ACV 1; ALPHA CONOTOXIN VC1.1; AM 336; ANTICONVULSIVE AGENT; CGX 1051; CGX 1160; CHI CONOTOXIN MR1A; CONANTOKIN G; CONOTOXIN; CONTRYPHAN VN; CONTULAKIN G; CORTICOSTEROID; GLACONTRYPHAN M; KAPPA CONOTOXIN PV11A; LOCAL ANESTHETIC AGENT; MARINE TOXIN; MORPHINE; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT; NARCOTIC ANALGESIC AGENT; NEUROTENSIN; NONSTEROID ANTIINFLAMMATORY AGENT; OMEGA CONOTOXIN CVID; OMEGA CONOTOXIN MVIIA; PLACEBO; TRICYCLIC ANTIDEPRESSANT AGENT; UNCLASSIFIED DRUG; XEN 2174;

ABSENCE OF SIDE EFFECTS; ANALGESIC ACTIVITY; ATAXIA; CANCER PAIN; CHRONIC PAIN; CLINICAL TRIAL; CONFUSION; CONUS SNAIL; DELIRIUM; DIZZINESS; DRUG EFFICACY; DRUG INDUCED HEADACHE; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG RESEARCH; DRUG SCREENING; DRUG SELECTIVITY; DRUG SPECIFICITY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; EPILEPSY; HUMAN; NAUSEA; NEUROPATHIC PAIN; NONHUMAN; PATIENT COMPLIANCE; PHARMACOPHORE; POSTOPERATIVE PAIN; PRIORITY JOURNAL; QUANTITATIVE STRUCTURE ACTIVITY RELATION; REVIEW; STRUCTURE ACTIVITY RELATION; UNSTEADINESS;

EID: 34447523350     PISSN: 17460441     EISSN: None     Source Type: Journal    
DOI: 10.1517/17460441.2.4.453     Document Type: Review

References (146)

1. DOKOUMETZIDIS A, AARONS L: Propagation of population PK and PD information using a bayesian approach: dealing with non-exchangeability. J. Pharmacokinet. Pharmacodyn. (2006) 33:29-48.
2. DOKOUMETZIDIS A, KARALIS V, ILIADIS A et al.: The heterogeneous course of drug transit through the body. Trends Pharmacol. Sci. (2004) 25:140-146.
3. DOKOUMETZIDIS A, KOSMIDIS K, ARGYRAKIS P et al.: Modeling and monte carlo simulations in oral drug absorption. Basic Clin. Pharmacol. Toxicol. (2005) 96:200-205.
4. DI L, KERNS EH: Profiling drug-like properties in discovery research. Curr. Opin. Chem. Biol. (2003) 7:402-408.
5. LIPINSKI CA: Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods. (2000) 44:235-249.
6. SILLERUD LO, LARSON RS: Design and structure of peptide and peptidomimetic antagonists of protein-protein interaction. Curr. Protein Pept. Sci. (2005) 6:151-169.
7. HUMMEL G, REINEKE U, REIMER U: Translating peptides into small molecules. Molecular BioSystems (2006) 2:499-508.
8. ORIVE G, GASCON AR, HERNANDEZ RM et al.: Techniques: new approaches to the delivery of biopharmaceuticals. Trends Pharmacol. Sci. (2004) 25:382-387.
9. FRY DC,VASSILEV LT: Targeting protein-protein interactions for cancer therapy. J. Mol. Med. (2005).
10. VASSILEV LT, VU BT, GRAVES B et al.: In vivo activation of the p53 pathway by small-molecule antagonists of mdm2. Science (2004) 303:844-848.
11. OLIVERA BM: E.E. Just lecture, 1996. Conus venom peptides, receptor and ion channel targets, and drug design: 50 million years of neuropharmacology. Mol. Biol. Cell. (1997) 8:2101-2109.
12. OL1VERA BM, RIVIER J, CLARK C et al.: Diversity of conus neuropeptides. Science. (1990) 249:257-263.
13. LIVETT BG, GAYLER KR, KHALIL Z: Drugs from the sea: conopeptides as potential therapeutics. Curr. Med. Chem. (2004) 11:1715-1723.
14. NORTON RS, OLIVERA BM: Conotoxins down under. Toxicon. (2006) 48:780-798.
15. OLIVERA BM: Conus peptides: Biodiversity-based discovery and exogenomics. J. Biol. Chem. (2006) 281:31173-31177.
16. BANDYOPADHYAY PK, GARRETT JE, SHETTY RP et al.: γ-glutamyl carboxylation: an extracellular posttranslational modification that antedates the divergence of molluscs, arthropods, and chordates. Proc. Natl. Acad. Sci. USA (2002) 99:1264-1269.
17. ESPIRITU DJ, WATKINS M, DIA-MONJE V et al.: Venomous cone snails: molecular phylogeny and the generation of toxin diversity. Toxicon. (2001) 39:1899-1916.
18. OLIVERA BM, WALKER C, CARTIER GE et al.: Speciation of cone snails and interspecific hyperdivergence of their venom peptides. Potential evolutionary significance of introns. Ann. NY Acad. Sci. (1999) 870:223-237.
19. WOODWARD SR, CRUZ LJ, OLIVERA BM et al.: Constant and hypervariable regions in conotoxin propeptides. Embo J. (1990) 9:1015-1020.
20. HASSON A, SHON KJ, OLIVERA BM et al.: Alterations of voltage-activated sodium current by a novel conotoxin from the venom of conus gloriamaris. J. Neurophysiol. (1995) 73:1295-1301.
21. HAMMAN JH, ENSLIN GM, KOTZE AF: Oral delivery of peptide drugs: barriers and developments. BioDrugs (2005) 19:165-177.
22. BUCZEK O, BULAJ G, OLIVERA BM: Conotoxins and the posttranslational modification of secreted gene products. Cell. Mol. Life Sci. (2005) 62:3067-3079.
23. GRANT MA, MORELLI XJ, RIGBY AC: Conotoxins and structural biology: a prospective paradigm for drug discovery. Curr. Protein Pept. Sci. (2004) 5:235-248.
24. FRANCO A, PISAREWICZ K, MOLLER C et al.: Hyperhydroxylation: a new strategy for neuronal targeting by venomous marine molluscs. Prog. Mol. Subcell. Biol. (2006) 43:83-103.
25. HURKO O, RYAN JL: Translational research in central nervous system drug discovery. NeuroRx (2005) 2:671-682.
26. BLACK MD: Therapeutic potential of positive ampa modulators and their relationship to ampa receptor subunits. A review of preclinical data. Psychopharmacology (Berl). (2005) 179:154-163.
27. PALMER AM, STEPHENSON FA: CNS drug discovery: challenges and solutions. Drug News Perspect. (2005) 18:51-57.
28. GAYLER K, SANDALL D, GREENING D et al.: Molecular prospecting for drugs from the sea. Isolating therapeutic peptides and proteins from cone snail venom. IEEE Eng. Med. Biol. Mag. (2005) 24:79-84.
29. LIVETT BG, SANDALL DW, KEAYS D et al.: Therapeutic applications of conotoxins that target the neuronal nicotinic acetylcholine receptor. Toxicon. (2006) 48:810-829.
30. VADALOUCA A, SIAFAKA I, ARGYRA E et al.: Therapeutic management of chronic neuropathic pain: an examination of pharmacologic treatment. Ann. NY Acad. Sci. (2006) 1088:164-186.
31. MILJANICH GP: Ziconotide: neuronal calcium channel blocker for treating severe chronic pain. Curr. Med. Chem. (2004) 11:3029-3040.
32. STAATS PS, YEARWOOD T, CHARAPATA SG et al.: Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or aids: a randomized controlled trial. JAMA (2004) 291:63-70.
33. ENDEAN R: Venomous cones. Aust. Nat. Hist. (1964) 14:400-403.
34. GARBER K: Peptide leads new class of chronic pain drugs. Nat. Biotechnol. (2005) 23:399.
35. ZAMPONI GW: New frontiers in managing chronic pain. Curr. Top. Med. Chem. (2005) 5:527.
36. JONES RM, BULAJ G: Conotoxins - new vistas for peptide therapeutics. Curr. Pharm. Des. (2000) 6:1249-1285.
37. FRANEY T: Novel compounds drive the market for neuropathic pain therapies 10 $1.25 billion by 2012. WWMR inc (2006).
38. WERMELING D, DRASS M, ELLIS D et al.: Pharmacokinetics and pharmacodynamics of intrathecal ziconotide in chronic pain patients. J. Clin. Pharmacol. (2003) 43:624-636.
39. HEADING CE: Ziconotide (ELAN pharmaceuticals). IDrugs (2001) 4:339-350.
40. WALLACE MS: Ziconotide: a new nonopioid intrathecal analgesic for the treatment of chronic pain. Expert Rev. Neurother. (2006) 6:1423-1428.
41. RAUCK RL, WALLACE MS, LEONG MS et al.: A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J. Pain Symptom Manage. (2006) 31:393-406.
42. SNUTCH TP: Targeting chronic and neuropathic pain: the N-type calcium channel comes of age. NeuroRx (2005) 2:662-670.
43. CAO YQ: Voltage-gated calcium channels and pain. Pain. (2006) 126:5-9.
44. MCINTOSH JM, OLIVERA BM, CRUZ LJ et al.: Gamma-carboxyglutamate in a neuroactive toxin. J. Biol. Chem. (1984) 259:14343-14346.
45. 2+ entry into neurons. J. Toxicol. Toxin Reviews (1990) 9:179-202.
46. SKOLNICK P, BOJE K, MILLER R et al.: Noncompetitive inhibition of N-methyl-D-aspartate by conantokin-g: Evidence for an allosteric interaction at polyamine sites. Journal of Neurochemistry (1992) 59:1516-1521.
47. CHANDLER P, PENNINGTON M, MACCECCHINI ML et al.: Polyamine-like actions of peptides derived from conantokin-g, an N-methyl-D-aspartare (nmda) antagonist. J. Biol. Chem. (1993) 268:17173-17178.
48. ZHOU LM, SZENDREI GI, FOSSOM LH et al.: Synthetic analogues of conantokin-g: NMDA antagonists acting through a novel polyamine-coupled site. J. Neurochem. (1996) 66:620-628.
49. RIGBYAC, BALEJA JD, FURJE BC et al.: Three-dimensional structure of a gamma-carboxyglutamic acid-containing conotoxin, conantokin g, from the marine snail conus geographus: the metal-free conformer. Biochemistry (1997) 36:6906-6914.
50. RIGBY AC, BALEJA JD, LI L et al.: Role of gamma-casboxyglutamic acid in the calcium-induced structural transition of conantokin G, a conotoxin from the marine snail conus geographus. Biochem. (1997) 36:15677-15684.
51. SKJAERBAEK N, NIELSEN KJ, LEWIS RJ et al.: Determination of the solution structures of conantokin-G and conantokin-T by CD and NMR spectroscopy. J. Biol. Chem. (1997) 272:2291-2299.
52. CHEN Z, BLANDL T, PROROK M et al.: Conformational changes in conantokin-g induced upon binding of calcium and magnesium as revealed by nmr structural analysis. J. Biol. Chem. (1998) 273:16248-16258.
53. MALMBERG AB, GILBERT H, MCCABE RT et al.: Powerful antinociceptive effects of the cone snail venom-derived subtype-selective nmda receptor antagonists conantokins G and T. Pain (2003) 101:109-116.
54. ALONSO D, KHALIL Z, SATKUNANTHAN N et al.: Drugs from the sea: conotoxins as drug leads for neuropathic pain and other neurological conditions. Mini Rev. Med. Chem. (2003) 3:785-787.
55. BOGIN O: Venom peptides and their mimetics as potential drug Modulator. (2005) 19:14-20.
56. CRAIG AG, NORBERG T, GRIFFIN D et al.: Contulakin-G, an O-glycosylated invertebrate neurotensin. J. Biol. Chem. (1999) 274:13752-13759.
57. LEWIS RJ, GARCIA ML: Therapeutic potential of venom peptides. Nat. Rev. Drug Discov. (2003) 2:790-802.
58. KANG J, LOW W, NORBERG T et al.: Total chemical synthesis and NMR characterization of the glycopeptide tx5a, a heavily post-translationally modified conotoxin, reveals that the glycan structure is α-D-gal-(→3)-α-D-galnac. Eur. J. Biochem. (2004) 271:4939-4949.
59. SANDALL DW, SATKUNANATHAN N, KEAYS DA et al.: A novel alpha-conotoxin identified by gene sequencing is active in suppressing the vascular response to selective stimulation of sensory nerves in vivo. Biochemistry (2003) 42:6904-6911.
60. JAKUBOWSKI JA, KEAYS DA, KELLEY WP et al.: Determining sequences and post-translational modifications of novel conotoxins in conus victoriae using cdna sequencing and mass spectrometry. J. Mass Spectrom. (2004) 39:548-557.
61. CHIVIAN E, ROBERTS CM, BERNSTEIN AS: The threat to cone snails. Science (2003) 302:391.
62. DUDA TF, JR., BINGHAM JP, LIVETT BG et al.: How much at risk are cone snails? Science. (2004) 303:955-957; author reply 955-957.
63. OLIVERA BM, R1VIER J, SCOTT JK et al.: Conotoxins. J. Biol. Chem. (1991) 266:22067-22070.
64. LANG PM, BURGSTAHLER R, HABERBERGER RV et al.: A conus peptide blocks nicotinic receptors of unmyelinated axons in human nerves. Neuroreport. (2005) 16:479-483.
65. SATKUNANATHAN N, LIVETT B, GAYLER K et al.: Alpha-conotoxin vcl. 1 alleviates neuropathic pain and accelerates functional recovery of injured neurones. Brain Res. (2005) 1059:149-158.
66. RESSLER KJ, NEMEROFF CB: Role of norepinephrine in the pathophysiology and treatment of mood disorders. Biol. Psychiatry. (1999) 46:1219-1233.
67. MCINTOSH JM, CORPUZ GO, LAYER RT et al.: Isolation and characterization of a novel conus peptide with apparent antinociceptive activity. J. Biol. Chem. (2000) 275:32391-32397.
68. NIELSEN CK, LEWIS RJ, ALEWOOD D et al.: Anti-allodynic efficacy of the chi-conopeptide, xen2174, in rats with neuropathic pain. Pain. (2005) 118:112-124.
69. ADAMS DJ, SMITH AB, SCHROEDER CI et al.: Omega-conotoxin cvid inhibits a pharmacologicly distinct voltage-sensitive calcium channel associated with transmitter release from preganglionic nerve terminals. J. Biol. Chem. (2003) 278:4057-4062.
70. SMITH MT, CABOT PJ, ROSS FB et al.: The novel N-type calcium channel blocker, am336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance p release in rat spinal cord slices. Pain. (2002) 96:119-127.
71. SCHROEDER CI, DOERING CJ, ZAMPONI GW et al.: N-type calcium channel blockers: novel therapeutics for the treatment of pain. Med. Chem. (2006) 2:535-543.
72. BAJORATH J: Integration of virtual and high-throughput screening. Nat. Rev. Drug Discov. (2002) 1:882-894.
73. BOCK JR, GOUGH DA: A new method to estimate ligand-receptor energetics. Mol. Cell Proteomics. (2002) 1:904-910.
74. GODDEN JW, FURR JR, XUE L et al.: Molecular similarity analysis and virtual screening by mapping of consensus positions in binary-transformed chemical descriptor spaces with variable dimensionality. J. Chem. Inf. Comput. Sci. (2004) 44:21-29.
75. KITCHEN DB, DECORNEZ H, FURR JR et al.: Docking and scoring in virtual screening for drug discovery: Methods and applications. Nat. Rev. Drug Discov. (2004) 3:935-949.
76. SHOICHET BK: Virtual screening of chemical libraries. Nature. (2004) 432:862-865.
77. MORELLI X, RIGBY AC: Acceleration of the drug discovery process: a combinatorial approach using nmr spectroscopy and virtual screening. Cur. Comp-Aid. Drug Design. (2007) In Press.
78. GRADL SN, FELIX JP, ISACOFF EY et al.: Protein surface recognition by rational design: Nanomolar ligands for potassium channels. J. Am. Chem. Soc. (2003) 125:12668-12669.
79. JAIN R, CHAWRAI S: Advancements in the anti-diabetes chemotherapeutics based on amino acids, peptides, and peptidomimetics. Mini Rev. Med. Chem. (2005) 5:469-477.
80. LEDUC AM, TRENT JO, WITTLIFF JL et al.: Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions. Proc. Natl. Acad. Sci. USA (2003) 100:11273-11278.
81. WATT PM: Screening for peptide drugs from the natural repertoire of biodiverse protein folds. Nat. Biotechnol. (2006) 24:177-183.
82. YIN H, LEE GI, SEDEY KA et al.: Terphenyl-based bak bh3 alpha-helical proteomimetics as low-molecular-weight antagonists of bcl-xl. J. Am. Chem. Soc. (2005) 127:10191-10196.
83. LUBBERS NL, CAMPBELL TJ, POLAKOWSKI JS et al.: Postischemic administration of CGX-1051, a peptide from cone snail venom, reduces infarct size in both rat and dog models of myocardial ischemia and reperfusion. J. Cardiovasc. Pharmacol. (2005) 46:141-146.
84. ZHANG SJ, YANG XM, LIU GS et al.: CGX-1051, a peptide from conus snail venom, attenuates infarction in rabbit hearts when administered at reperfusion. J. Cardiovasc. Pharmacol. (2003) 42:764-771.
85. NORTON RS, PENNINGTON MW, WOLFF H: Potassium channel blockade by the sea anemone toxin SHK for the treatment of multiple sclerosis and other autoimmune diseases. Curr. Med. Chem. (2004) 11:3041-3052.
86. + channel. J. Biol. Chem. (2000) 275:24639-24644.
87. WITT KA, DAVIS TP: CNS drug delivery: opioid peptides and the blood-brain barrier. Aaps J. (2006) 8:E76-88.
88. BARR RK, BOEHM I, ATTWOOD PV et al.: The critical features and the mechanism of inhibition of a kinase interaction motif-based peptide inhibitor of jnk. J. Biol. Chem. (2004) 279:36327-36338.
89. BARR RK, HOPKINS RM, WATT PM et al.: Reverse two-hybrid screening identifies residues of ink required for interaction with the kinase interaction motif of ink-interacting protein-1. J. Biol. Chem. (2004) 279:43178-43189.
90. MATTHEWS T, SALGO M, GREENBERG M et al.: Enfuvirtide: the first therapy to inhibit the entry of HIV-1 into host cd4 lymphocytes. Nat. Rev. Drug Discov. (2004) 3:215-225.
91. CHAN B, GREENAN G, MCKEON F et al.: Identification of a peptide fragment of dscr1 that competitively inhibits calcineurin activity in vitro and in vivo. Proc. Natl Acad. Sci. USA (2005) 102:13075-13080.
92. HANSSON K, MA X., ELIASSON L et al.: The first gla-containing contryphan: a selective l-type calcium ion channel blocker isolated from the venom of conus rnarmoreus. J. Biol. Chem. (2004) 279:32453-32463.
93. BUCZEK O, YOSHIKAMI D, WATKINS M et al.: Characterization of D-amino-acid-containing excitatory conotoxins and redefinition of the i-conotoxin superfamily. Febs J. (2005) 272:4178-4188.
94. LOVELACE ES, ARMISHAW CJ, COLGRAVE ML et al.: Cyclic mria: a stable and potent cyclic conotoxin with a novel topological fold that targets the norepinephrine transporter. J. Med. Chem. (2006) 49:6561-6568.
95. NICKE A, SAMOCHOCKI M, LOUGHNAN ML et al.: α-Conotoxins epi and auib switch subtype selectivity and activity in native versus recombinant nicotinic acetylcholine receptors. FEBS Lett. (2003) 554:219-223.
96. QUIRAM PA, SINE SM: Structural elements in α-conotoxin imi essential for binding to neuronal α7 receptors. J. Biol. Chem. (1998) 273:11007-11011.
97. NICKE A, LOUGHNAN ML, MILLARD EL et al.: Isolation, structure, and activity of gid, a novel α 4/7-conotoxin with an extended N-terminal sequence. J. Biol. Chem. (2003) 278:3137-3144.
98. KASHEVEROV IE, ZHMAK MN, VULFIUS CA et al.: α-Conotoxin analogs with additional positive charge show increased selectivity towards torpedo californica and some neuronal subtypes of nicotinic acetylcholine receptors. Febs J. (2006) 273:4470-4481.
99. DEECHONGKIT S, KELLY JW: The effect of backbone cyclization on the thermodynamics of beta-sheet unfolding: Stability optimization of the pin ww domain. J. Am. Chem. Soc. (2002) 124:4980-4986.
100. DEECHONGKIT S, NGUYEN H, POWERS ET et al.: Context-dependent contributions of backbone hydrogen bonding to beta-sheet folding energetics. Nature. (2004) 430:101-105.
101. DEECHONGKIT S, POWERS ET, YOU SL et al.: Controlling the morphology of cross beta-sheet assemblies by rational design. J. Am. Chem. Soc. (2005) 127:8562-8570.
102. CLARK RJ, FISCHER H, DEMPSTER L et al.: Engineering stable peptide toxins by means of backbone cyclization: stabilization of the alpha-conotoxin MII. Proc. Natl. Acad. Sci. USA (2005) 102:13767-13772.
103. HRUBY VJ, BALSE PM: Conformational and topographical considerations in designing agonist peptidomimetics from peptide leads. Curr. Med. Chem. (2000) 7:945-970.
104. YIN H, HAMILTON AD: Strategies for targeting protein-protein interactions with synthetic agents. Angew. Chem. Int. Ed. Engl. (2005) 44:4130-4163.
105. BODEN P, EDEN JM, HODGSON J et al.: Use of a dipeptide chemical library in the development of non-peptide tachykinin NK3 receptor selective antagonists. J. Med. Chem. (1996) 39:1664-1675.
106. HORWELL D, PRITCHARD M, RAPHY J et al.: 'Targeted' molecular diversity: design and development of non-peptide antagonists for cholecystokinin and tachykinin receptors. Immunopharmacology. (1996) 33:68-72.
107. HORWELL DC, HOWSON W, RATCLIFFE GS et al.: The design of dipeptide helical mimetics: the synthesis, tachykinin receptor affinity and conformational analysis of 1,1,6-trisubstituted indanes. Bioorg. Med. Chem. (1996) 4:33-42.
108. ORNER BP, ERNST JT, HAMILTON AD: Toward proteomimetics: terphenyl derivatives as structural and functional mimics of extended regions of an alpha-helix. J. Am. Chem. Soc. (2001) 123:5382-5383.
109. WALENSKY LD, KUNG AL, ESCHER I et al.: Activation of apoptosis in vivo by a hydrocarbon-stapled bh3 helix. Science. (2004) 305:1466-1470.
110. WALENSKY LD, PITTER K, MORASH Jet al.: A stapled bid bh3 helix directly binds and activates bax. Mol. Cell. (2006) 24:199-210.
111. ZHAO L, CHMIELEWSKI J: Inhibiting protein-protein interactions using designed molecules. Curr. Opin. Struct. Biol. (2005) 15:31-34.
112. PELLECCHIA M, SEM DS, WUTHRICH K: NMR in drug discovery. Nat. Rev. Drug Discov. (2002) 1:211-219.
113. ABRAHAMIAN E, FOX PC, NAERUM L et al.: Efficient generation, storage, and manipulation of fully flexible pharmacophore multiplets and their use in 3-D similarity searching. J. Chem. Inf. Comput. Sci. (2003) 43:458-468.
114. MARTIN YC: 3D database searching in drug design. J. Med. Chem. (1992) 35:2145-2154.
115. RIPKA AS, RICH DH: Peptidomimetic design. Curr. Opin. Chem. Biol. (1998) 2:441-452.
116. RIPKA AS, SATYSHUR KA, BOHACEK RS et al.: Aspartic protease inhibitors designed from computer-generated templates bind as predicted. Org Lett. (2001) 3:2309-2312.
117. DEBNATH AK: Quantitative structure-activity relationship (QSAR) paradigm - Hansch era to new millennium. Mini Rev. Med. Chem. (2001) 1:187-195.
118. FRANKE L, BYVATOV E, WERZ O et al.: Extraction and visualization of potential pharmacophore points using support vector machines: application to ligand-based virtual screening for COX-2 inhibitors. J. Med. Chem. (2005) 48:6997-7004.
119. TSUCHIDA K, CHAKI H, TAKAKURA T et al.: Discovery of nonpeptidic small-molecule ap-1 inhibitors: Lead hopping based on a three-dimensional pharmacophore model. J. Med. Chem. (2006) 49:80-91.
120. SCHNEIDER G, FECHNER U: Computer-based de novo design of drug-like molecules. Nat. Rev. Drug. Discov. (2005) 4:649-663.
121. BAELL JB, FORSYTH SA, GABLE RW et al.: Design and synthesis of type-iii mimetics of omega-conotoxin gvia, J. Comput. Aided Mol. Des. (2001) 15:1119-1136.
122. + channels. Biochem. Biophys. Res. Commun. (2003) 303:238-246.
123. HANSSON K, FURIE B, FURIE BC et al.: Isolation and characterization of three novel gla-containing conus marmoreus venom peptides, one with a novel cysteine pattern. Biochem. Biophys. Res. Commun. (2004) 319:1081-1087.
124. PALLAGHY PK, NORTON RS: The cyclic contryphan motif cpxxpxc, a robust scaffold potentially useful as an omega-conotoxin mimic. Biopolymers. (2000) 54:173-179.
125. PALLAGHY PK, MELNIKOVA AP, JIMENEZ EC et al.: Solution structure of contryphan-r, a naturally occurring disulfide- bridged octapeptide containing D-tryptophan: comparison with protein loops. Biochemistry. (1999) 38:11553-11559.
126. MASSILIA GR, SCHININA ME, ASCENZI P et al.: Contryphan-vn: a novel peptide from the venom of the mediterranean snail conus ventricosus. Biochem. Biophys. Res. Commun. (2001) 288:908-913.
127. GRANT MA, HANSSON K, FURIE BC et al.: The metal-free and calcium-bound structures of a gamma-carboxyglutamic add-containing contryphan from conus marmoreus, glacontryphan-M. J. Biol. Chem. (2004) 279:32464-32473.
128. + channel modulator. Biopolymers. (2004) 74:189-198.
129. 2+ channels. J. Bioenerg. Biomembr. (1998) 30:319-334.
130. IRWIN JJ, SHOICHET BK: Zinc - a free database of commercially available compounds for virtual screening. J. Chem. Inf. Model. (2005) 45:177-182.
131. SINGH J, ADAMS S, CARTER MB et al.: Rational design of potent and selective VLA-4 inhibitors and their utility in the treatment of asthma. Curr. Top Med. Chem. (2004) 4:1497-1507.
132. SINGH J, VAN VLIJMEN H, LEE WC et al.: 3D QSAR (comfa) of a series of potent and highly selective VLA-4 antagonists. J. Comput. Aided Mol. Des. (2002) 16:201-211.
133. SCHROEDER CI, SMYTHE ML, LEWIS RJ: Development of small molecules that mimic the binding of omega-conotoxins at the N-type voltage-gated calcium channel. Mol. Divers. (2004) 8:127-134.
134. HANSCH C, MALONEY, PP, FUJITA T, MUIR RM: Correlation of biological activity of phenoxyacetic acids with hammett substituent constants and partition coefficients. Nature (1962) 194:178-180.
135. PARDRIDGE WM: The blood-brain barrier: bottleneck in brain drug development. NeuroRx (2005) 2:3-14.
136. SU Y, SINKO PJ: Drug delivery across the blood-brain barrier: why is it difficult? How to measure and improve it? Expert Opin. Drug Deliv. (2006) 3:419-435.
137. LIEDERER BM, FUCHS T, VANDER VELDE D et al.: Effects of amino acid chirality and the chemical linker on the cell permeation characteristics of cyclic prodrogs of opioid peptides. J. Med. Chem. (2006) 49:1261-1270.
138. DREWS J: Drug discovery: a historical perspective. Science (2000) 287:1960-1964.
139. DREWS J, RYSER S: The role of innovation in drug development. Nat. Biotechnol. (1997) 15:1318-1319.
140. BRADFORD JR, WESTHEAD DR: Improved prediction of protein-protein binding sites using a support vector machines approach. Bioinformatics (2005) 21:1487-1494.
141. FOLKERS GE, VAN BUUREN BN, KAPTEIN R: Expression screening, protein purification and NMR analysis of human protein domains for structural genomics. J. Struct. Funct. Genomics (2004) 5:119-131.
142. LUNDSTROM K: Structural genomics on membrane proteins: mini review. Comb. Chem. High Throughput Screen. (2004) 7:431-439.
143. DREWS II: Drug discovery today - and tomorrow. Drug Discov. Today (2000) 5:2-4.
144. CHEN L, YIN H, FAROOQI B et al.: P53 α-helix mimetics antagonize p53/MDM2 interaction and activate p53. Mol. Cancer Ther. (2005) 4:1019-1025.
145. ARKIN MR, RANDAL M, DELANO WL et al.: Binding of small molecules to an adaptive protein-protein interface. Proc. Natl. Acad. Sci USA (2003) 100:1603-1608.
146. ARKIN MR, WELLS JA: Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nat. Rev. Drug Discov. (2004) 3:301-317.