Transformative concepts for drug design: Target wrapping

Transformative Concepts for Drug Design: Target Wrapping

Volumn , Issue , 2010, Pages 1-230

  Fernández, Ariel ^a  

^a Rice University   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 84891448400     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1007/978-3-642-11792-3     Document Type: Book

References (363)

1. Anfinsen CB (1973) Principles that govern the folding of protein chains. Science 181:223-230
2. Fernández A, Sosnick TR, Colubri A (2002) Dynamics of hydrogen-bond desolvation in folding proteins. J Mol Biol 321:659-675
3. Chandler D (2005) Interfaces and the driving force of hydrophobic assembly. Nature 437:640-647
4. Jewett A, Pande VS, Plaxco KW (2003) Cooperativity, smooth energy landscapes and the origins of topology-dependent protein folding rates. J Mol Biol 326:247-253
5. Scalley-Kim M, Baker D (2004) Characterization of the folding energy landscapes of computer generated proteins suggests high folding free energy barriers and cooperativity may be consequences of natural selection. J Mol Biol 338:573-583
6. Fernández A, Colubri A, Berry RS (2002) Three-body correlations in protein folding: The origin of cooperativity. Physica A 307:235-259
7. Fernández A, Kostov K, Berry RS (1999) From residue matching patterns to protein folding topographies: General model and bovine pancreatic trypsin inhibitor. Proc Natl Acad Sci USA 96:12991-12996
8. Fernández A, Colubri A, Berry RS (2000) Topology to Geometry in protein folding: Betalactoglobulin. Proc Natl Acad Sci USA 97:14062-14066
9. Fernández A, Kardos J, Goto J (2003) Protein folding: Could hydrophobic collapse be coupled with hydrogen-bond formation? FEBS Lett 536:187-192
10. Fernández A (2001) Conformation-dependent environments in folding proteins. J Chem Phys 114:2489-2502
11. Fernández A, Kardos J, Scott R, Goto Y, Berry RS (2003) Structural defects and the diagnosis of amyloidogenic propensity. Proc Natl Acad Sci USA 100:6446-6451
12. Fernández A (2004) Keeping dry and crossing membranes. Nat Biotechnol 22:1081-1084
13. Pietrosemoli N, Crespo A, Fernández A (2007) Dehydration propensity of order-disorder intermediate regions in soluble proteins. J Proteome Res 6:3519-3526
14. Fernández A, Scott R (2003) Dehydron: A structure-encoded signal for protein interactions. Biophys J 85:1914-1928
15. Avbelj F, Baldwin RL (2003) Role of backbone solvation and electrostatics in generating preferred peptide backbone conformations: distributions of phi. Proc Natl Acad Sci USA 100:5742-5747
16. Krantz BA, Moran LB, Kentsis A, Sosnick TR (2000) D/H amide kinetic isotope effects reveal when hydrogen bonds form during protein folding. Nat Struct Biol 7:62-71
17. Fersht A (2000) Transition-state structure as a unifying basis in protein-folding mechanisms: Contact order, chain topology, stability, and the extended nucleus mechanism. Proc Natl Acad Sci USA 97:1525-1929
18. Plaxco KW, Simmons KT, Baker D (1998) Contact order, transition state placement and the refolding rates of single domain proteins. J Mol Biol 277:985-994
19. Fernández A, Scott LR (2003). Adherence of packing defects in soluble proteins. Phys Rev Lett 91:018102
20. Fernández A, Zhang X, Chen J (2008) Folding and wrapping soluble proteins: Exploring the molecular basis of cooperativity and aggregation. Prog Nucleic Acids Res Transl Sci 83:57-87
21. Fernández A, Scheraga HA (2003) Insufficiently dehydrated hydrogen bonds as determinants of protein interactions. Proc Natl Acad Sci USA 100:113-118
22. Fernández A, Berry RS (2003) Proteins with H-bond packing defects are highly interactive with lipid bilayers: Implications for amyloidogenesis. Proc Natl Acad Sci USA 100:2391-2396
23. Deremble C, Lavery R (2005) Macromolecular recognition. Curr Opin Struct Biol 15:171-175
24. Ma B, Elkayam T, Wolfson H, Nussinov R (2003) Protein-protein interactions: Structurally conserved residues distinguish between binding sites and exposed protein surfaces. Proc Natl Acad Sci USA 100:5772-5777
25. Fernández A (2003) What caliber pore is like a pipe? Nanotubes as modulators of ion gradients. J Chem Phys 119:5315-5319
26. Despa F, Fernández A, Berry RS (2004) Dielectric modulation of biological water. Phys Rev Lett 93:228104
27. Demetri G (2002) Efficacy and safety of imatinib mesyalte in advanced gastrointestinal stromal tumors. N Engl J Med 347:472-480
28. Fernández A, Sanguino A, Peng Z et al (2007) An anticancer C-kit kinase inhibitor is reengineered to make it more active and less cardiotoxic. J Clin Invest 117:4044-4054
29. Baldwin RL (2003) In search of the energetic role of peptide hydrogen bonds. J Biol Chem 278:17581-17588
30. Powers ET, Deechongkit S, Kelly JW (2006) Backbone-backbone H-bonds make contextdependent contributions to protein folding kinetics and thermodynamics: Lessons from amideto-ester mutations. In: Peptide Solvation and H-bonds, Baldwin RL, Baker D, eds, Adv Protein Chem 72:40-79, Elsevier Academic Press, San Diego, California
31. Fernández A, Berry RS (2002) Extent of Hydrogen-bond protection in folded proteints: A constraint on packing architectures. Biophys J 83:2475-2481
32. Pietrosemoli N, Crespo A, Fernández A (2007) Dehydration propensity of order-disorder intermediate regions in soluble proteins. J Proteome Res 6:3519-3526
33. Fernández A, Scheraga HA (2003) Insufficiently dehydrated hydrogen bonds as determinants for protein interactions. Proc Nat Acad Sci USA 100:113-118
34. + channels share common features. Neuron 1:997-1001
35. Fernández A, Berry RS (2002) Extent of Hydrogen-bond protection in folded proteins: A constraint on packing architectures. Biophys J 83:2475-2481
36. Pentelute BL, Gates ZP, Tereshko V et al (2008) X-ray structure of snow flea antifreeze protein determined by racemic crystallization of synthetic protein enantiomers. J Am Chem Soc 130:9695-9701
37. Adzhubei AA, Sternberg M J E (1993) Left-handed polyproline II helices commonly occur in globular proteins. J Mol Biol 229:472-493
38. Shi Z, Woody RW, Kallenbach NR (2002) Is polyproline II a major backbone conformation in unfolded proteins? In: Unfolded Proteins, Rose G, ed, Adv Protein Chem 62:163-240
39. Kumar MD (2006) ProTherm and ProNIT: thermodynamic databases for proteins and proteinnucleic acid interactions. Nucleic Acids Res 34:D204-D206
40. Doig AJ, Williams DH (1991) Is the hydrophobic effect stabilizing or destabilizing in proteins: The contribution of disulphide bonds to protein stability. J Mol Biol 217:389-398
41. Betz SF (1993) Disulfide bonds and the stability of globular proteins. Protein Sci 2:1551-1558
42. Fernández A, Scott R (2003) Adherence of packing defects in soluble proteins. Phys Rev Lett 91:018102
43. Anfinsen CB (1973) Principles that govern the folding of protein chains. Science 181:223-230
44. Fernández A, Sosnick TR, Colubri A (2002) Dynamics of hydrogen-bond desolvation in folding proteins. J Mol Biol 321:659-675
45. Chandler D (2005) Interfaces and the driving force of hydrophobic assembly. Nature 437:640-647
46. Jewett A, Pande VS, Plaxco KW (2003) Cooperativity, smooth energy landscapes and the origins of topology-dependent protein folding rates. J Mol Biol 326:247-253
47. Scalley-Kim M, Baker D (2004) Characterization of the folding energy landscapes of computer generated proteins suggests high folding free energy barriers and cooperativity may be consequences of natural selection. J Mol Biol 338:573-583
48. Fernández A, Colubri A, Berry RS (2002) Three-body correlations in protein folding: The origin of cooperativity. Physica A 307:235-259
49. Fernández A, Kostov K, Berry RS (1999) From residue matching patterns to protein folding topographies: General model and bovine pancreatic trypsin inhibitor. Proc Natl Acad Sci USA 96:12991-12996
50. Fernández A, Colubri A, Berry RS (2000) Topology to Geometry in protein folding: Betalactoglobulin. Proc Natl Acad Sci USA 97:14062-14066
51. Fernández A, Kardos J, Goto J (2003) Protein folding: Could hydrophobic collapse be coupled with hydrogen-bond formation? FEBS Lett 536:187-192
52. Fernández A (2001) Conformation-dependent environments in folding proteins. J Chem Phys 114:2489-2502
53. Avbelj F, Baldwin RL (2003) Role of backbone solvation and electrostatics in generating preferred peptide backbone conformations: Distributions of phi. Proc Natl Acad Sci USA 100:5742-5747
54. Fernández A (2004) Keeping dry and crossing membranes. Nat Biotechnol 22:1081-1084
55. Krantz BA, Moran LB, Kentsis A, Sosnick TR (2000) D/H amide kinetic isotope effects reveal when hydrogen bonds form during protein folding. Nat Struct Biol 7:62-71
56. Plaxco KW, Simmons KT, Baker D (1998) Contact order, transition state placement and the refolding rates of single domain proteins. J Mol Biol 277:985-994
57. Fersht A (2000) Transition-state structure as a unifying basis in protein-folding mechanisms: Contact order, chain topology, stability, and the extended nucleus mechanism. Proc Natl Acad Sci USA 97:1525-1929
58. Fernández A, Scott LR (2003) Adherence of packing defects in soluble proteins. Phys Rev Lett 91:018102
59. Fernández A (2003) What caliber pore is like a pipe? Nanotubes as modulators of ion gradients. J Chem Phys 119:5315-5319
60. Fernández A, Shen M, Colubri A, Sosnick TR, Freed KF (2003) Large-scale context in protein folding: Villin headpiece. Biochemistry 42:664-671
61. Duan Y, Kollman PA (1998) Pathways to a protein folding intermediate observed in a 1-microsecond simulation in aqueous solution. Science 282:740-744
62. Baldwin RL (2002) Making a network of hydrophobic clusters. Science 295:1657-1658
63. Nemethy G, Steinberg IZ, Scheraga HA (1963) The influence of water structure and hydrophobic contacts on the strength of side-chain hydrogen bonds in proteins. Biopolymers 1:43-69
64. Fernández A, Berry RS (2002) Extent of hydrogen-bond protection in folded proteins: A constraint on packing architectures. Biophys J 83:2475-2481
65. Novotny J, Bruccoleri R, Karplus M (1984) Analysis of incorrectly folded protein models. Implications for structure predictions. J Mol Biol 177:787-818
66. Daggett V, Levitt M (1992) A model of the molten globule state from molecular dynamics simulations. Proc Natl Acad Sci USA 89:5142-5146
67. Brooks CL, Case D (1993) Simulations of peptide conformational dynamics and thermodynamics. Chem Rev 93:2487-2502
68. Fernández A, Rogale K (2004) Sequence-space selection of cooperative model proteins. J Phys A: Math & Gen 37:197-202
69. Kuwata K, Shastry R, Cheng H, Hoshino M, Batt CA, Goto Y, Roder H (2001) Structural and kinetic characterization of early folding events in beta-lactoglobulin. Nat Struct Biol 8:151-155
70. Nymeyer H, Garcia AE, Onuchic JN (1998) Folding funnels and frustration in off-lattice minimalist protein landscapes. Proc Natl Acad Sci 95:5921-5928
71. Onuchic JN, Luthey-Schulten Z, Wolynes PG (1997) Theory of protein folding: The energy landscape perspective. Annu Rev Phys Chem 48:545-600
72. Chan HS, Dill KA (1997) From Levinthal to pathways to funnels. Nat Struct Biol 4:10-19
73. Fernández A, Colubri A, Berry RS (2001) Topologies to geometries in protein folding: Hierarchical and nonhierarchical scenarios. J Chem Phys 114:5871-5888
74. Shi Z, Krantz BA, Kallenbach N, Sosnick TR (2002) Contribution of hydrogen bonding to protein stability estimated from isotope effects. Biochemistry 41:2120-2129
75. Pietrosemoli N, Crespo A, Fernández A (2007) Dehydration propensity of order-disorder intermediate regions in soluble proteins. J Proteome Res 6:3519-3526
76. Despa F, Fernández A, Berry RS (2004) Dielectric modulation of biological water. Phys Rev Lett 93:228104
77. Fernandez A, Zhang X, Chen J (2008) Folding and wrapping soluble proteins: Exploring the molecular basis of cooperativity and aggregation. Prog Mol Biol Transl Sci 83:53-88
78. Otting G, Liepinsh E, Wüthrich K (1991) Protein hydration in aqueous solution. Science 254:974-980
79. Qiu W, Kao Y, Zhang L et al (2006) Protein surface hydration mapped by site-specific mutations. Proc Natl Acad Sci USA 103:13979-13984
80. Makarov V, Andrews BV, Smith PE, Pettitt BM (2000) Residence times of water molecules in the hydration sites of myoglobin. Biophys J 79:2966-2974
81. Chandler D (2005) Interfaces and the driving force of hydrophobic assembly. Nature 437:640-647
82. Cheng Y, Rossky PJ (1998) Surface topography dependence of biomolecular hydrophobic hydration. Nature 392:696-699
83. Liu P, Huang X, Zhou R, Berne BJ (2005) Observation of a dewetting transition in the collapse of the melitin tetramer. Nature 437:159-162
84. Fernández A, Scheraga HA (2003) Insufficiently dehydrated hydrogen bonds as determinants of protein interactions. Proc Natl Acad Sci USA 100:113-118
85. Fernández A, Kardos J, Scott R, Goto Y, Berry RS (2003) Structural defects and the diagnosis of amyloidogenic propensity. Proc Natl Acad Sci USA 100:6446-6451
86. Hetenyi C, Van Der Spoel D (2006) Blind docking of drug-sized compounds to proteins with up to a thousand residues. FEBS Lett 580:1447-1450
87. Fernández A, Berry RS (2004) Molecular dimension explored in evolution to promote proteomic complexity. Proc Natl Acad Sci USA 101:13460-13465
88. Fernández A, Scott RL (2003) Dehydron: A structurally encoded signal for protein interaction. Biophys J 85:1914-1928
89. Fernández A, Scott LR (2003) Adherence of packing defects in soluble proteins. Phys Rev Lett 91:018102
90. Yu H, Rosen MK, Schreiber SL (1993) 1H and 15 N assignments and secondary structure of the Src SH3 domain. FEBS Lett 324:87-92
91. Vijay-Kumar S, Bugg CE, Cook WJ (1987) Structure of ubiquitin refined at 1.8 angstrom resolution. J Mol Biol 194:531-544
92. Van Der Spoel D, Van Maaren P, Larsson P, Timneanu N (2006) Thermodynamics of hydrogen bonding in hydrophilic and hydrophobic media. J Phys Chem B 110:4393-4398
93. Sheu S, Yang D, Selzle H, Schlag EW (2003) Energetics of hydrogen bonds in peptides. Proc Natl Acad Sci USA 100:12683-12687
94. Rizzo RC, Jorgensen WL (1999) OPLS All-atom model for amines: Resolution of the amine hydration problem. J Am Chem Soc 121:4827-4836
95. Jorgensen WL, Chandrasekhar J, Madura J, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926-935
96. Lindahl E, Hess B, Van Der Spoel D (2001) GROMACS 3.0: A package for molecular simulation and trajectory analysis. J Mol Model 7:302-317
97. Fernández A, Chen J, Crespo A (2007) Solvent-exposed backbone loosens the hydration shell of soluble folded proteins. J Chem Phys 126:245103
98. Denisov V, Halle B (1995) Protein hydration dynamics in aqueous solution. A comparison of bovine pancreatic trypsin inhibitor and ubiquitin by oxygen-17 spin relaxation dispersion. J Mol Biol 245:682-697
99. Lum K, Chandler D, Weeks JD (1999) Hydrophobicity at small and large length scales. J Phys Chem B 103:4570-4577
100. Mason PE, Neilson GW, Dempsey CE, Barnes AC, Cruickshank JM (2003) The hydration structure of guanidinium and thiocyanate ions: Implications for protein stability. Proc Natl Acad Sci USA 100:4557-4561
101. Kocher JP, Prevost M, Wodak S, Lee B (1996) Properties of the protein matrix revealed by the free energy of cavity formation. Structure 4:1517-1529
102. Fernández A, Sosnick TR, Colubri A (2002) Dynamics of hydrogen-bond desolvation in folding proteins. J Mol Biol 321:659-675
103. Fernández A, Sosnick TR, Colubri A (2002) Dynamics of hydrogen-bond desolvation in folding proteins. J Mol Biol 321:659-675
104. Fernández A, Scheraga HA (2003) Insufficiently dehydrated hydrogen bonds as determinants of protein interactions. Proc Natl Acad Sci USA 100:113-118
105. Fernández A, Scott LR (2003) Adherence of packing defects in soluble proteins. Phys Rev Lett 91:018102
106. Fernández A, Berry RS (2004) Molecular dimension explored in evolution to promote proteomic complexity. Proc Natl Acad Sci USA 101:13460-13465
107. Fernández A, Scott RL (2003) Dehydron: A structurally encoded signal for protein interaction. Biophys J 85:1914-1928
108. Fernández A (2004) Keeping dry and crossing membranes. Nat Biotechnol 22:1081-1084
109. Fernández A, Scott RL, Berry RS (2006) Packing defects as selectivity switches for drugbased protein inhibitors. Proc Natl Acad Sci USA 103:323-328
110. Fernández A, Kardos J, Scott R, Goto Y, Berry RS (2003) Structural defects and the diagnosis of amyloidogenic propensity. Proc Natl Acad Sci USA 100:6446-6451
111. Fernández A, Berry RS (2003) Proteins with hydrogen-bond packing defects are highly interactive with lipid bilayers: Implications for amyloidogenesis. Proc Natl Acad Sci USA 100:2391-2396
112. Deremble C, Lavery R (2005) Macromolecular recognition. Curr Opin Struct Biol 15:171-175
113. Ma B, Elkayam T, Wolfson H, Nussinov R (2003) Protein-protein interactions: Structurally conserved residues distinguish between binding sites and exposed protein surfaces. Proc Natl Acad Sci USA 100:5772-5777
114. Ma B, Pan Y, Gunasekaran K, Venkataraghavan RB, Levine AJ, Nussinov R (2005) Comparison of the protein-protein interfaces in the p53-DNA crystal structures: Towards elucidation of the biological interface. Proc Natl Acad Sci USA 102:3988-3993
115. Rajamani D, Thiel S, Vajda S, Camacho CJ (2004) Anchor residues in protein-protein interactions. Proc Natl Acad Sci USA 101:11287-11292
116. Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN (2005) Flexible nets: The roles of intrinsic disorder in protein interaction networks. FEBS J 272:5129-5148
117. Iakoucheva LM, Dunker AK (2003) Order, disorder, and flexibility: Prediction from protein sequence. Structure (London) 11:1316-1317
118. Dunker AK, Obradovic Z (2001) The protein trinity-linking function and disorder. Nat Biotechnol 19:805-806
119. Wade RC, Gabdoulline RR, Lüdemann SK, Lounnas V (1998) Electrostatic steering and ionic tethering in enzyme-ligand binding: Insights from simulations. Proc Natl Acad Sci USA 95:5942-5949
120. Ho WC, Fitzgerald MX, Marmorstein R (2006) Structure of the p53 core domain dimer bound to DNA. J Biol Chem 281:20494-20502
121. Pietrosemoli N, Crespo A, Fernández A (2007) Dehydration propensity of order-disorder intermediate regions in soluble proteins. J Prot Res 6:3519-3526
122. Lindahl E, Hess B, Van Der Spoel D: GROMACS 3.0: A package for molecular simulations and trajectory analysis. J Mol Model 2001, 7:302-317
123. Fernández A (2003) What caliber pore is like a pipe? Nanotubes as modulators of ionic gradients. J Chem Phys 119:5315-5319
124. Ben-Naim A (1980) Hydrophobic Interactions. Plenum Press, New York
125. Debye P (1929) Polar Molecules. Dover, New York
126. Mason PE, Neilson GW, Dempsey CE, Barnes AC, Cruickshank, JM (2003) The hydration structure of guanidinium and thiocyanate ions: Implications for protein stability in aqueous solution. Proc Natl Acad Sci USA 100:4557-4561
127. Kabsch W, Mannherz HG, Suck D, Pai EF, Holmes KC (1990) Atomic structure of the actin: DNase I complex. Nature 347:37-44
128. Meador WE, Means AR, Quiocho FA (1993) Modulation of calmodulin plasticity in molecular recognition on the basis of x-ray structures. Science 262:1718-1721
129. Williams RS, Green R, Glover JN (2001) Crystal structure of the BRCT repeat region from the breast cancer-associated protein BRCA1. Nat Struct Biol 8:838-842
130. Zahn R, Liu A, Luhrs T et al (2000) NMR solution structure of the human prion protein. Proc Natl Acad Sci USA 97:145-150
131. Schnuchel A, Wiltscheck R, Eichinger L, Schleicher M, Holak, TA (1995) Structure of severin domain 2 in solution. J Mol Biol 247:21-27
132. Glover JN, Harrison SC (1995) Crystal structure of the heterodimeric bZIP transcription factor c-Fos-c-Jun. bound to DNA. Nature 373:257-261
133. Lavigne P, Crump MP, Gagne SM et al (1998) Insights into the mechanism of heterodimerization from the 1H-NMR solution structure of the c-Myc-Max heterodimeric leucine zipper. J Mol Biol 281:165-181
134. Dobson CM (1999) Protein misfolding, evolution and disease. Trends Biochem Sci 24:329-332
135. Dobson CM (2001) The structural basis of protein folding and its links with human disease. Philos Trans R Soc Lond B 356:133-145
136. Fändrich M, Dobson CM (2002) The behavior of polyamino acids reveals an inverse side chain effect in amyloid structure formation. EMBO J 21:5682-5690
137. Sunde M, Blake C C F (1998) From the globular to the fibrous state: protein structure and structural conversion in amyloid formation. Q Rev Biophys 31:1-39
138. Dobson CM (2002) Protein misfolding diseases: Getting out of shape. Nature 418:729-730
139. Richardson JS, Richardson DC (2002) Natural β-sheet proteins use negative design to avoid edge-to-edge aggregation. Proc Natl Acad Sci USA 99:2754-2759
140. Avbelj F, Baldwin RL (2003) Role of backbone solvation and electrostatics in generating preferred peptide backbone conformations: Distributions of phi. Proc Natl Acad Sci USA 100:5742-5747
141. Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95:13363-13383
142. Nelson R, Sawaya M, Balbirnie M et al (2005) Structure of the cross-beta spine of amyloidlike fibrils. Nature 435:773-778
143. Krishnan R, Lindquist SL (2005) Structural insights into a yeast prion illuminate nucleation and strain diversity. Nature 435:765-772
144. Fernández A, Scott R, Berry RS (2004) The nonconserved wrapping of conserved folds reveals a trend towards increasing connectivity in proteomic networks. Proc Natl Acad Sci USA 101:2823-2827
145. Fernández A, Berry RS (2004) Molecular dimension explored in evolution to promote proteomic complexity. Proc Natl Acad Sci USA 101:13460-13465
146. Lynch M, Conery JS (2003) The origins of genome complexity. Science 302:1401-1404
147. Kondrashov FA, Koonin EV (2004) A common framework for understanding the origin of genetic dominance and evolutionary fates of gene duplications. Trends Genet 20:287-290
148. Liang H, Rogale-Plazonic K, Chen J, Li WH, Fernández A (2008) Protein under-wrapping causes dosage sensitivity and decreases gene duplicability. PLoS Genet 4:e11
149. Papp B, Pal C, Hurst LD (2003) Dosage sensitivity and the evolution of gene families in yeast. Nature 424:194-197
150. Fernández A, Scheraga H (2003) Insufficiently dehydrated hydrogen bonds as determinants for protein interactions. Proc Natl Acad Sci USA 100:113-118
151. Bartel D (2009) MicroRNAs: Target recognition and regulatory functions. Cell 136:215-233
152. Fernández A (2004) Keeping dry and crossing membranes. Nat Biotechnol 22:1081-1084
153. Veitia RA (2002) Exploring the etiology of haploinsufficiency. Bioessays 24:175-184
154. Veitia RA (2004) Gene dosage balance: Deletions, duplications and dominance. Trends Genet 21:33-35
155. Su AI, Wiltshire T, Batalov S et al (2004) A gene atlas of the mouse and human proteinencoding transcriptomes. Proc Natl Acad Sci USA 101:6062-6067
156. Birney E, Andrews D, Caccamo M et al (2006) Ensembl 2006. Nucleic Acids Res 34:D556-D561
157. Yang Z, Nielsen R (2000) Estimating synonymous and nonsynonymous substitution rates under realistic evolutionary models. Mol Biol Evol 17:32-43
158. Friedman RC, Farth KK, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92-105
159. Lewis B, Burge C, Bartel D (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120:15-20
160. Fernández A, Chen J (2009) Human capacitance to dosage imbalance: coping with inefficient selection. Genome Res 19:2185-2192
161. Grimson A, Farth KK, Johnston WK et al (2007) MicroRNA target specificity in mammals: Determinants beyond seed pairing. Mol Cell 27:91-105
162. Aloy P, Ceulemans H, Stark A, Russell RB (2003) The relationship between sequence and interaction divergence in proteins. J Mol Biol 332:989-998
163. Gu Z, Nicolae D, Lu HH, Li W-H (2002) Rapid divergence in expression between duplicate genes inferred from microarray data. Trends Genet 18:609-613
164. Chen F, Li W-H (2001) Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. Am J Hum Genet 68:444-456
165. Gao L, Innan H (2004) Very low gene duplication rate in the yeast genome. Science 306:1367-1370
166. Surmacz E, Bartucci M (2005) Role of estrogen receptor alpha in modulating IGF-I receptor signaling and function in breast cancer. J Exp Clin Cancer Res 23:385-394
167. Fernández A (2005) Incomplete protein packing as a selectivity filter in drug design. Structure 13:1829-1836
168. Fernández A, Scott R, Berry RS (2004) The nonconserved wrapping of conserved folds reveals a trend towards increasing connectivity in proteomic networks. Proc Natl Acad Sci USA 101:2823-2827
169. Fernández A, Berry RS (2004) Molecular dimension explored in evolution to promote proteomic complexity. Proc Natl Acad Sci USA 101:13460-13465
170. Fernández A, Berry RS (2002) Extent of hydrogen-bond protection in folded proteins: A constraint on packing architectures. Biophys J 83:2475-2481
171. Fernández A, Berry RS (2003) Proteins with hydrogen-bond packing defects are highly interactive with lipid bilayers: Implications for amyloidogenesis. Proc Natl Acad Sci USA 100:2391-2396
172. Fernández A, Rogale K, Scott LR, Scheraga HA (2004) Inhibitor design by wrapping packing defects in HIV-1 proteins. Proc Natl Acad Sci USA 101:11640-11645
173. Deremble C, Lavery R (2005) Macromolecular recognition. Curr Opin Str Biol 15:171-175
174. Fernández A, Scheraga HA (2003) Insufficiently dehydrated hydrogen bonds as determinants of protein interactions. Proc Natl Acad Sci USA 100:113-118
175. Ban Y-E, Edelsbrunner H, Rudolph J (2006) Interface surfaces for protein-protein complexes. J Assoc Comp Mach 53:361-378
176. Adesokan AA, Roberts VA, Lee KW, Linz RD, Briggs JM (2004) Prediction of HIV-1 integrase/viral DNA interactions in the catalytic domain by fast molecular docking. J Med Chem 47:821-828
177. Kortemme T, Baker D (2004) Computational design of protein-protein interactions. Curr Opin Chem Bio 8:91097
178. Kortvelyesi T, Silberstein M, Dennis S, Vajda S (2003) Improved mapping of protein binding sites. J Comput Aided Mol Des 17:173-186
179. Lu L, Lu H, Skolnick J (2002) Multiprospector: An algorithm for the prediction of proteinprotein interactions by multimeric threading. Proteins Struct Funct Genet 49:350-364
180. Sen TZ, Kloczkowski A, Jernigan RL et al (2004) Predicting binding sites of hydrolaseinhibitor complexes by combining several methods. BMC Bioinform 5:205-215.
181. Huber R (1979) Conformational flexibility in protein molecules. Nature 280:538-539
182. Dunker KA, Brown C, Obradovic Z (2002) Identification and function of usefully disordered proteins. Adv Protein Chem 62:25-49
183. Verkhivker G, Bouzida D, Gehehaar D, Rejto P, Freer ST, Rose P (2003) Simulating disorderorder transition in molecular recognition of unstructured proteins: Where folding meets binding. Proc Natl Acad Sci USA 100:5148-5153
184. Fernández A, Crespo A (2008) Protein wrapping: A molecular marker for association, aggregation and drug design. Chem Soc Rev 37:2372-2382
185. Stevens RC (2004) Long live structural biology. Nat Struct Mol Biol 11:293-295
186. Fauman EB, Hopkins A, Groom C (2003) Structural bioinformatics in drug discovery. In: Structural Bioinformatics, Bourne P, Weissig H, eds, Wiley-Liss, New York
187. Wlodawer A, Vondrasek J (1998) Inhibitors of HIV-1 protease: A major success of structureassisted drug design. Annu Rev Biophys Biomol Struct 27:249-284
188. Arkin MR, Wells JA (2004) Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nat Rev Drug Discov 3:301-317
189. Katz BA (2000) Structural basis for selectivity of a small molecule, S1-Binding, submicromolar inhibitor of urokinase-type plasminogen activator. Chem Biol 7:299-307
190. Steinmetzer T, Hauptmann J, Sturzebecher J (2001) Expert Opin Invest Drugs 10:845-864
191. Nicholls A, Sharp KA, Honig B (1991) Protein folding and association: Insights from the interfacial and thermodynamic properties of hydrocarbons. Proteins Struct Funct Genet 11:281-196
192. Liang J, Edelsbrunner H, Woodward C (1998) Anatomy of protein pockets and cavities: Measurement of binding site geometry and implications for ligand design. Protein Sci 7:1884-1897
193. Lee B, Richards FM (1971) The interpretation of protein structures: Estimation of static accessibility. J Mol Biol 55:379-400
194. Fernández A, Scott LR (2003) Adherence of packing defects in soluble proteins. Phys Rev Lett 91:18102
195. Fernández A, Scott LR (2003) Dehydron: A structure encoded signal for protein interactions. Biophys J 85:1914-1928
196. Munshi S, Chen Z, Li Y et al (1998) Rapid X-ray diffraction analysis of HIV-1 proteaseinhibitor complexes: Inhibitor exchange in single crystals of the bound enzyme. Acta Crystallogr D 54:1053-1060
197. Mount DW (2001) Bioinformatics, Cold Spring Harbor Laboratory Press, New York
198. Karaman MW, Herrgard S, Treiber DK et al (2008) A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 26:127-132
199. NIH/NCBI website for the structural alignment program Cn3D. http://www.ncbi.nlm.nih.gov/structure/CN3D/cn3d.shtml
200. Schindler T, Bornmann W, Pellicena P et al (2000) Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 289:1938-1942
201. Attoub S, Rivat C, Rodrigues S et al (2002) The C-kit tyrosine kinase inhibitor STI-571 for colorectal cancer therapy. Cancer Res 62:4879-4883
202. Skene RJ, Kraus ML, Scheibe DN (2004) Structural basis for autoinhibition and STI-571 inhibition of C-kit tyrosine kinase. J Biol Chem 279:31655-31663
203. Perlmutter RM, Marth JD, Lewis DB et al (1988) Structure and expression of lck transcripts in human lymphoid cells. J Cell Biochem 38:117-126
204. Li J, Johnson D, Sliskovic D, Roth B (2004) Contemporary Drug Synthesis. Wiley Interscience, Hoboken
205. Fernández A, Sanguino A, Peng Z et al (2007) An anticancer C-kit kinase inhibitor is reengineered to make it more active and less cardiotoxic. J Clin Invest 117:4044-4054
206. Dancey J, Sausville EA (2003) Issues and progress with protein kinase inhibitors for cancer treatment. Nat Rev Drug Discov 2:296-313
207. Levitski A, Gazit A (1995) Tyrosine kinase inhibition: An approach to drug development. Science 267:1782-1788
208. Tibes R, Trent J, Kurzrock R (2005) Tyrosine kinase inhibitors and the dawn of molecular cancer therapeutics. Annu Rev Pharmacol Toxicol 45:357-84
209. Gibbs J, Oliff A (1994) Pharmaceutical research in molecular oncology. Cell 79:193-198
210. Donato NJ, Talpaz M (2000) Clinical use of tyrosine kinase inhibitors: Therapy for chronic myelogenous leukemia and other cancers. Clin Cancer Res 6:2965-2966
211. Fabian MA, Biggs WH, Treiber DK et al (2005) A small molecule kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23:329-336
212. Gambacorti-Passerini C, Le Coutre P, Mologni L et al (1997) Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. Blood Cells Mol Dis 23:380-394
213. Schindler T, Bornmann W, Pellicena P et al (2000) Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 289:1938-1942
214. Attoub S, Rivat C, Rodrigues S et al (2002) The C-kit tyrosine kinase inhibitor STI-571 for colorectal cancer therapy. Cancer Res 62:4879-4883
215. De Matteo RP (2002) The GIST of targeted cancer therapy: A tumor (gastrointestinal stromal tumor), a mutated gene (c-kit), and a molecular inhibitor (STI571). Ann Surg Oncol 9:831-839
216. Skene RJ, Kraus ML, Scheibe DN et al (2004) Structural basis for autoinhibition and STI-571 inhibition of C-kit tyrosine kinase. J Biol Chem 279:31655-31663
217. Tuveson DA, Willis NA, Jacks T et al (2001) STI571 inactivation of the gastrointestinal stromal tumor C-kit oncoprotein: Biological and clinical implications. Oncogene 20:5054-5058
218. Chen JP, Zhang X, Fernández A (2007) Molecular basis for specificity in the druggable kinome: Sequence-based analysis. Bioinformatics 23:563-572
219. Fernández A, Sanguino A, Peng Z et al (2007) An anticancer C-kit kinase inhibitor is reengineered to make it more active and less cardiotoxic. J Clin Invest 117:4044-4054
220. Kerkela R, Grazette L, Yacobi R et al (2006) Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12:908-916
221. Druker BJ (2004) Molecularly targeted therapy: Have the floodgates opened? Oncologist 9:357-360
222. Fernández A, Scheraga HA (2003) Insufficiently dehydrated hydrogen bonds as determinants of protein interactions. Proc Natl Acad Sci USA 100:113-118
223. 60c-src tyrosine kinase activities using a continuous assay: Autoactivation of the enzyme is an intermolecular autophosphorylation process. Biochemistry 34:14843-14851
224. Songyang Z, Carraway KL, Eck M et al (1995) Catalytic specificity of protein-tyrosine kinases is critical for selective signalling. Nature 373:536-539
225. Clarkson B, Strife A, Wisniewski D, Lambek CL, Liu C (2003) Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategy. Leukemia 17:1211-1262
226. Prenen H, Deroose C, Vermaelen P, Sciot R, Debiec-Rychter M (2006) Establishment of a mouse gastrointestinal stromal tumour model and evaluation of response to Imatinib by small animal positron emission tomography. Anticancer Res 26:1247-1252
227. Baines CP, Molkentin JD (2005) Stress signaling pathways that modulate cardiac myocyte apoptosis. J Mol Cell Cardiol 38:47-62
228. Scheuermann-Freestone M, Simon Freestone N, Langenickel T et al (2001) A new model of congestive heart failure in the mouse due to chronic volume overload. Eur J Heart Fail 3:535-543
229. Bain J, McLauchlan H, Eliott M, Cohen P (2003) The specificities of protein kinase inhibitors: An update. Biochem J 371:199-204
230. Druker BJ (2004) Molecularly targeted therapy: Have the floodgates opened? Oncologist 9:357-360
231. Hopkins AL, Mason JS, Overington JP (2006) Can we rationally design promiscuous drugs? Curr Opin Str Biol 16:127-136
232. Huse M, Kuriyan J (2002) The conformational plasticity of protein kinases. Cell 109:275-282
233. Knight ZA, Shokat KM (2005) Features of selective kinase inhibitors. Chem Biol 12:621-637
234. Chothia C (1974) Hydrophobic bonding and accessible surface area in proteins. Nature 248:338-339
235. Whittle PJ, Blundell TL (1994) Protein structure-based drug design. Annu Rev Biophys Biomol Struct 23:349-375
236. Feng BY, Shelat A, Doman TN, Guy RK, Shoichet BK (2005) High throughput assays for promiscuous inhibitors. Nat Chem Biol 1:146-148
237. Zhang X, Crespo A, Fernández A (2008) Trung promiscuous kinase inhibitors into safer drugs. Trends Biotechnol 26:295-300
238. Chen JP, Zhang X, Fernández A (2007) Molecular basis for specificity in the druggable kinome: sequence-based analysis. Bioinformatics 23:563-572
239. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912-1934
240. Braken C, Iakoucheva LM, Romero PR, Dunker AK (2004) Combining prediction, computation and experiment for the characterization of protein disorder. Curr Opin Struct Biol 14:570-576
241. Fernández A, Berry RS (2004) Molecular dimension explored in evolution to promote proteomic complexity. Proc Natl Acad Sci USA 101:13460-13465
242. Fabian MA, Biggs WH, Treiber DK et al (2005) A small molecule kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23:329-336
243. Karaman MW, Herrgard S, Treiber DK et al (2008) A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 26:127-132
244. Bonneau R, Straus CE, Rohl CA et al (2002) De novo prediction of three-dimensional structures for major protein families. J Mol Biol 322:65-78
245. Chivian D, Kim DE, Malmstrom L et al (2005) Prediction of CASP6 structures using automated Robetta protocols. Proteins 61 (Suppl 7):157-166
246. Higgins DG, Thompson JD, Gibson TJ (1996) Using CLUSTAL for multiple sequence alignments. Method Enzymol 266:383-402
247. Fraczkiewicz R, Braun W (1998) Exact and efficient analytical calculation of the accessible surface areas and their gradient for macromolecules. J Comput Chem 19:319-333
248. Ooi T, Oobatake M, Nemethy G, Scheraga HA (1987) Accessible surface area as a measure of the thermodynamic parameters of hydration of peptides. Proc Natl Acad Sci USA 84:3086-3090
249. Ma B, Elkayam T, Wolfson T, Nussinov R (2003) Protein-protein interactions structurally conserved residues distinguish between binding sites and exposed protein surfaces. Proc Natl Acad Sci USA 100:5772-5777
250. Fernández A, Maddipati S (2006) A priori inference of cross reactivity for drug-targeted kinases. J Med Chem 49:3092-3100
251. Fernández A, Sosnick TR, Colubri A (2002) Dynamics of hydrogen bond desolvation in protein folding. J Mol Biol 321:659-675
252. Fernández A (2004) Keeping dry and crossing membranes. Nat Biotechnol 22:1081-1084
253. Dancey J, Sausville EA (2003) Issues and progress with protein kinase inhibitors for cancer treatment. Nat Rev Drug Discov 2:296-313
254. Levitski A, Gazit A (1995) Tyrosine kinase inhibition: An approach to drug development. Science 267:1782-1788
255. Tibes R, Trent J, Kurzrock R (2005) Tyrosine kinase inhibitors and the dawn of molecular cancer therapeutics. Annu Rev Pharmacol Toxicol 45:357-384
256. Gibbs J, Oliff A (1994) Pharmaceutical research in molecular oncology. Cell 79:193-198
257. Donato NJ, Talpaz M (2000) Clinical use of tyrosine kinase inhibitors: Therapy for chronic myelogenous leukemia and other cancers. Clin Cancer Res 6:2965-2966
258. Roth BL, Sheffler DJ, Kroeze WK (2004) Magic shotguns versus magic bullets: Selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov 3:353-359
259. Frantz S (2005) Drug discovery: Playing dirty. Nature 437:942-943
260. Keith CT, Borisy AA, Stockwell BR (2005) Multicomponent therapeutics for networked systems. Nat Rev Drug Discov 4:71-78
261. Mencher SK, Wang LG (2005) Promiscuous drugs compared to selective drugs (promiscuity can be a virtue). BMC Clin Pharmacol 5:3-9
262. McGovern SL, Helfand BT, Feng B, Shoichet BK (2003) A specific mechanism of nonspecific inhibition. J Med Chem 46:4265-4272
263. Feng BY, Shelat A, Doman TN et al (2005) High-throughput assays for promiscuous inhibitors. Nat Chem Biol 1:146-148
264. Force T, Krause D, Van Etten RA (2007) Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 7:332-344
265. Fernández A, Sanguino A, Peng Z et al (2007) An anticancer C-kit kinase inhibitor is reengineered to make it more active and less cardiotoxic. J Clin Invest 117:4044-4054
266. Demetri GD (2007) Structural reengineering of imatinib to decrease cardiac risk in cancer therapy. J Clin Invest 117:3650-3653
267. Crunkhorn S (2008) Anticancer drugs: Redesigning kinase inhibitors. Nat Rev Drug Discov 7:120-121
268. Hopkins AL, Mason J, Overington J (2006) Can we rationally design promiscuous drugs? Curr Opin Struct Biol 16:127-136
269. Hampton T (2004) 'Promiscuous' anticancer drugs that hit multiple targets may thwart resistance. J Am Med Assoc 292:419-422
270. Hopkins AL, Ren J, Milton J et al (2004) Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved drug resistance properties. J Med Chem 47:5912-5922
271. Owens J (2006) Screening: Dirty drugs' secrets uncovered. Nat Rev Drug Discov 5:542
272. Fabian MA, Biggs WH, Treiber DK et al (2005) A small molecule kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23:329-336
273. Karaman MW, Herrgard S, Treiber DK et al (2008) A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 26:127-132
274. Fedorov O, Marsden B, Pogacic V et al (2007) A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci USA 104:20523-20528
275. MacDonald ML, Lamerdin J, Owens S et al (2006) Identifying off-targets effects and hidden phenotypes of drugs in human cells. Nat Chem Biol 2:329-337
276. Brunton LL, Lazo JS, Parker KL (2006) Goodman & Gilman's The Pharmacological Basis of Therapeutics. 11th ed. McGraw-Hill, New York
277. Rishton GM (2005) Failure and success in modern drug discovery: guiding principles in the establishment of high probability of success drug discovery organizations. Med Chem 1:519-527
278. Kerkela R, Grazette L, Yacobi R et al (2006) Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12:908-916
279. Fedorov O, Sundstrom M, Marsden B, Knapp S (2007) Insights for the development of specific kinase inhibitors by targeted structural genomics. Drug Discov Today 12:365-372
280. Bogoyevitch MA, Fairlie DP (2007) A new paradigm for protein kinase inhibition: blocking phosphorylation without directly targeting ATP binding. Drug Discov Today 12:622-633
281. Crespo A, Fernández A (2007) Kinase packing defects as drug targets. Drug Discov Today 12:917-923
282. Chen J, Zhang X, Fernández A (2007) Molecular basis for specificity in the druggable kinome: Sequence-based analysis. Bioinformatics 23:563-572
283. Griffin JD (2005) Interaction maps for kinase inhibitors. Nat Biotechnol 23:308-309
284. Liu Y, Gray NS (2006) Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2:358-364
285. Noble ME, Endicott JA, Johnson LN (2004) Protein kinase inhibitors: Insights into drug design from structure. Science 303:1800-1805
286. Torrance CJ, Jackson PE, Montgomery E et al (2000) Combinatorial chemoprevention of intestinal neoplasia. Nat Med 6:1024-1028
287. Erlichman C, Hidalgo M, Boni JB et al (2006) Phase I study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor, in patients with advanced solid tumors. J Clin Oncol 24:2252-2260
288. Wissner A, Overbeek E, Reich MF et al (2003) Synthesis and structure-activity relationships of 6, 7-disubstituted 4-anilinoquinoline-3- carbonitriles. The design of an orally active, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor-2 (HER-2). J Med Chem 46:49-63
289. Zhang X, Crespo A, Fernández A (2008) Turning promiscuous kinase inhibitors into safer drugs. Trends Biotechnol 26:295-301
290. Fernández A, Maddipati S (2006) The a-priori inference of cross reactivity for drug targeted kinases. J Med Chem 49:3092-3100
291. Butcher EC (2004) Systems biology in drug discovery. Nat Biotechnol 22:1253-1259
292. Butcher EC (2005) Can cell systems biology rescue drug discovery? Nat Rev Drug Discov 4:461-467
293. Kitano H (2007) A robustness-based approach to systems-oriented drug design. Nat Rev Drug Discov 6:202-209
294. Volgestein B, Kinzler KW (2004) Cancer genes and the pathway they control. Nat Med 10:789-799
295. Kitano H (2004) Biological robustness. Nat Rev Genet 5:826-837
296. Carlson JM, Doyle J (2002) Complexity and robustness. Proc Natl Acad Sci USA 99:2538-2545
297. Hellerstein MK (2008) Exploiting complexity and the robustness of network architecture for drug discovery. J Pharmacol Exp Ther 325:1-9
298. Seidman A (2002) Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20:1215-1221
299. Martel CL (2006) Bevacizumab-related toxicities: Association of hypertension and proteinuria. Commun Oncol 3:90-93
300. Hampton T (2004) 'Promiscuous' anticancer drugs that hit multiple targets may thwart resistance. J Am Med Assoc 292:419-422
301. Motzer RJ, Michaelson MD, Redman BG et al (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24:16-24
302. Joensuu, H. (2007) Cardiac toxicity of sunitinib. Lancet 370:1978-1980
303. Chu TF, Rupnick MA, Kerkela R et al (2007) Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 370:2011-2019
304. Dancey J, Sausville EA (2003) Issues and progress with protein kinase inhibitors for cancer treatment. Nat Rev Drug Discov 2:296-313
305. Tibes R, Trent J, Kurzrock R (2005) Tyrosine kinase inhibitors and the dawn of molecular cancer therapeutics. Annu Rev Pharmacol Toxicol 45:357-384
306. Schindler T, Bornmann W, Pellicena P et al (2000) Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 289:1938-1942
307. Schiffer CA (2007) BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia. N Engl J Med 357:258-265
308. Crespo A, Fernández A (2007) Kinase packing defects as drug targets. Drug Discov Today 12:917-923
309. Teague S (2003) Implications of protein flexibility for drug discovery. Nat Rev Drug Discov 2:527-541
310. Damm KL, Carlson HA (2007) Exploring experimental sources of multiple protein conformations in structure-based drug design. J Am Chem Soc 129:8225-8235
311. Hornak V, Simmerling C (2007) Targeting structural flexibility in HIV-1 protease inhibitor binding. Drug Discov Today 12:132-138
312. Erickson J (2004) Lessons in molecular recognition: The effects of ligand and protein flexibility on molecular docking accuracy. J Med Chem 47:45-55
313. Noble ME, Endicott JA, Johnson LN (2004) Protein kinase inhibitors: Insights into drug design from structure. Science 303:1800-1805
314. Pietrosemoli N, Crespo A, Fernández A (2007) Dehydration propensity of order-disorder intermediate regions in soluble proteins. J Proteome Res 6:3519-3526
315. Chen J, Zhang X, Fernández A (2007) Molecular basis for specificity in the druggable kinome: Sequence-based analysis. Bioinformatics 23:563-572
316. Fernández A (2004) Keeping dry and crossing membranes. Nat Biotechnol 22:1081-1084
317. Fernández A, Sanguino A, Peng Z et al (2007) An anticancer C-kit kinase inhibitor is reengineered to make it more active and less cardiotoxic. J Clin Invest 117:4044-4054
318. Crunkhorn S (2008) Anticancer drugs: Redesigning kinase inhibitors. Nat Rev Drug Discov 7:120-121
319. Fernández A, Sanguino A, Peng Z et al (2007) Rational drug redesign to overcome drug resistance in cancer therapy: Imatinib moving target. Cancer Res 67:4028-4033
320. Demetri GD, Von Mehren M, Blanke CD et al (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472-480
321. Kerkela R, Grazette L, Yacobi R et al (2006) Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12:908-916
322. Force T, Krause D, Van Etten RA (2007) Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 7:332-344
323. Demetri GD (2007) Structural reengineering of imatinib to decrease cardiac risk in cancer therapy. J Clin Invest 117:3650-3653
324. Fernández A, Bazan S, Chen J (2009) Taming the induced folding of drug-targeted kinases. Trends Pharmacol Sci 30:66-71
325. Widakowich C, De Castro G, De Azambuja E, Dinh P, Awada A (2007) Review: Side effects of approved molecular targeted therapies in solid cancers. Oncologist 12:1443-1455
326. Schmidinger M, Zielinski CC, Vogl UM et al (2008) Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 26:5204-5212
327. Lacouture ME (2006) Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 6:803-812
328. Verheul HM, Pinedo HM (2007) Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 7:475-485
329. Force T, Krause D, Van Etten RA (2007) Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 7:332-344
330. Force T, Kerkela R (2008) Cardiotoxicity of the new cancer therapeutics - mechanisms of, and approaches to, the problem. Drug Discov Today 13:778-784
331. Kerkela R, Grazette L, Yacobi R et al (2006) Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12:908-916
332. Chu TF, Rupnick MA, Kerkela R et al (2007) Cardiotoxicity associated with tyrosine kinase inhibitor sunitnib. Lancet 370:2011-2019
333. Fernández A, Crespo A, Tiwari A (2009) Is there a case for selectively promiscuous anticancer drugs? Drug Discov Today 14:1-5
334. Zhang X, Crespo A, Fernández A (2008) Turning promiscuous kinase inhibitors into safer drugs. Trends Biotechnol 26:295-301
335. Dancey J, Sausville EA (2003) Issues and progress with protein kinase inhibitors for cancer treatment. Nat Rev Drug Discov 2:296-313
336. Levitzki A, Gazit A (1995) Tyrosine kinase inhibition: An approach to drug development. Science 267:1782-1788
337. Fernández A, Sanguino A, Peng Z et al (2007) An anticancer C-kit kinase inhibitor is re-engineered to make it more active and less cardiotoxic. J Clin Invest 117:4044-4054
338. Kitano H (2007) A robustness-based approach to systems-oriented drug design. Nat Rev Drug Discov 6:202-209
339. Torchilin VP (2006) Multifunctional nanocarriers. Adv Drug Del Rev 58:1532-1555
340. Langer R (2001) Drug delivery: Drugs on target. Science 293:58-59
341. Allen TM, Cullis PR (2004) Drug delivery systems: Entering the mainstream. Science 303:1818-1822
342. Deninger M, Buchdunger E, Druker BJ (2005) The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105:2640-2653
343. Dancey JE, Chen HX (2006) Strategies for optimizing combinations of molecularly targeted anticancer drugs. Nat Rev Drug Discov 5:649-659
344. Keith CT, Borisky AA, Stockwell BR (2005) Multicomponent therapeutics for networked systems. Nat Rev Drug Discov 4:71-78
345. Zimmermann GR, Lehar J, Keith CT (2007) Multi-target therapeutics: When the whole is greater than the sum of the parts. Drug Discov Today 12:34-42
346. Verweij J, Casali P, Kotasek D et al (2007) Imatinib does not induce cardiac left ventricular failure in gastrointestinal stromal tumours patients: Analysis of EORTC-ISG-AGITG study 62005. Eur J Cancer 43:974-978
347. Atallah E, Durand JB, Kantarjian H, Cortes J (2007) Congestive heart failure is a rare event in patients receiving imatinib. Blood 110:1233-1237
348. Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125-134
349. O'Neill E, Rushworth L, Baccarini M, Kolch W (2004) Role of the kinase MST2 in suppression of apoptosis by the Proto-Oncogene product Raf-1. Science 306:2267-2270
350. Dhillon AS, Hagan S, Rath O, Kolch W (2007) MAP kinase signalling pathways in cancer. Oncogene 26:3279-3290
351. Chen J, Zhang X, Fernández A (2007) Molecular basis for specificity in the druggable kinome: Sequence-based analysis. Bioinformatics 23:563-572
352. Faivre S, Demetri G, Sargent W, Raymond E (2007) Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 6:734-745
353. O'Neill EE, Matallanas D, Kolch W (2005) Mammalian sterile 20-like kinases in tumor suppression: An emerging pathway. Cancer Res 65:5485-5487
354. Karaman MW, Herrgard S, Treiber DK et al (2008) A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 26:127-132
355. Kantarjian H, Jabbour E, Grimley J, Kirkpatrick P (2006) Dasatinib. Nat Rev Drug Discov 5:717-718
356. Fernández A, Sessel S (2009) Selective antagonism of anticancer drugs for side-effect removal. Trends Pharmacol Sci 30:403-410
357. Gazdar A (2009) Personalized medicine and inhibition of EGFR signaling in lung cancer. New Engl J Med 361:1018-1020
358. Janne PA, Gray N, Settleman J (2009) Factors underlying sensitivity of cancers to small molecule kinase inhibitors. Nat Rev Drug Discov 8:709-723
359. Fernández A, Sanguino A, Peng Z et al (2007) Rational drug design to overcome drug resistance in cancer therapy: Imatinib moving target. Cancer Res 67:4028-4033
360. Hubbard SR (2004) Oncogenic mutations in B-Raf: Some losses yield gains. Cell 116, 764-766
361. Chandler D (2005) Interfaces and the driving force of hydrophobic assembly. Nature 437:640-647
362. Debye P (1929) Polar Molecules. Dover, New York
363. Wells JA, McClendon CL (2007) Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450:1001-1009