Conformational flexibility models for the receptor in structure based drug design

Current Pharmaceutical Design

Volumn 9, Issue 20, 2003, Pages 1635-1648

  Teodoro, M L ^a   Kavraki, L E ^b  

^a RICE UNIVERSITY   (United States)

^b Rice University   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DRUG; DRUG RECEPTOR; PROTEIN;

ACCURACY; CHEMICAL ANALYSIS; CONFORMATIONAL TRANSITION; CONTROLLED STUDY; DATA BASE; DRUG BINDING SITE; DRUG CONFORMATION; DRUG DESIGN; DRUG RECEPTOR BINDING; DRUG STRUCTURE; EXPERIMENTAL MODEL; MATHEMATICAL COMPUTING; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PHARMACOPHORE; PREDICTION; PRINCIPAL COMPONENT ANALYSIS; PRIORITY JOURNAL; PROBLEM SOLVING; PROTEIN STRUCTURE; REVIEW; SCORING SYSTEM; SCREENING TEST; SIMULATION; STRUCTURE ANALYSIS; X RAY CRYSTALLOGRAPHY;

DRUG DESIGN; MODELS, CHEMICAL; PROTEIN CONFORMATION; RECEPTORS, CELL SURFACE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0041989635     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/1381612033454595     Document Type: Review

References (132)

1. Fischer E. Einfluss der Configuration auf die Wirkung der Enzyme. Ber Dtsch Chem Ges 1894; 27: 2985.
2. Blow DM. Structure and Mechanism of Chymotrypsin. Acc Chem Res 1976; 9: 145-52.
3. Huber R, Bode W. Structural basis of the activation and action of trypsin. Acc Chem Res 1978; 11: 114-22.
4. Hubbard SJ, Campbell SF, Thornton JM. Molecular recognition. Conformational analysis of limited proteolytic sites and serine proteinase protein inhibitors. J Mol Biol 1991; 220: 507-30.
5. Amit AG, Mariuzza RA, Phillips SE, Poljak RJ. Three-dimensional structure of an antigen-antibody complex at 2.8 A resolution. Science 1986; 233: 747-53.
6. Koshland DE. Application of a theory of enzyme specificity to protein synthesis. Proc Natl Acad Sci USA 1958; 44: 98-104.
7. Weber PC, Ohlendorf DH, Wendoloski JJ, Salemme FR. Structural origins of high-affinity biotin binding to streptavidin. Science 1989; 243: 85-8.
8. Wlodawer A, Vondrasek J. Inhibitors of HIV-1 protease: a major success of structure-assisted drug design. Annu Rev Bioph Biom 1998; 27: 249-84.
9. Bystroff C, Kraut J. Crystal structure of unliganded Escherichia coli dihydrofolate reductase. Ligand-induced conformational changes and cooperativity in binding. Biochemistry-US 1991; 30: 2227-39.
10. Wilson DK, Tarle I, Petrash JM, Quiocho FA. Refined 1.8 A structure of human aldose reductase complexed with the potent inhibitor zopolrestat. Proc Natl Acad Sci USA 1993; 90: 9847.
11. Betts MJ, Sternberg MJ. An analysis of conformational changes on protein-protein association: implications for predictive docking. Protein Eng 1999; 12: 271-83.
12. Murray CW, Baxter CA, Frenkel AD. The sensitivity of the results of molecular docking to induced fit effects: Application to thrombin, thermolysin and neuraminidase. J Comput Aid Mol Des 1999; 13: 547-62.
13. Najmanovich R, Kuttner J, Sobolev V, Edelman M. Side-chain flexibility in proteins upon ligand binding. Proteins 2000; 39: 261-8.
14. Zhao S, Goodsell DS, Olson AJ. Analysis of a data set of paired uncomplexed protein structures: new metrics for side-chain flexibility and model evaluation. Proteins 2001; 43: 271-9.
15. Fradera X, Cruz X, Silva CHTP, Gelpi JL, Luque FJ, Orozco M. Ligand-induced changes in the binding site of proteins. Bioinformatics 2002; 18: 939-48.
16. Vazquez-Laslop N, Zheleznova EE, Markham PN, Brennan RG, Neyfakh AA. Recognition of multiple drugs by a single protein: a trivial solution of an old paradox. Biochem Soc T 2000; 28: 517-20.
17. Ma B, Kumar S, Tsai CJ, Nussinov R. Folding funnels and binding mechanisms. Protein Eng 1999; 12: 713-20.
18. Ma B, Shatsky M, Wolfson HJ, Nussinov R. Multiple diverse ligands binding at a single protein site: a matter of pre-existing populations. Protein Sci 2002; 11: 184-97.
19. Ma B, Wolfson HJ, Nussinov R. Protein functional epitopes: hot spots, dynamics and combinatorial libraries. Curr Opin Struct Biol 2001; 11: 364-9.
20. Bursavich MG, Rich DH. Designing non-peptide peptidomimetics in the 21st century: inhibitors targeting conformational ensembles. J Med Chem 2002; 45: 541-58.
21. Verkhivker GM, Bouzida D, Gehlhaar DK, Rejto PA, Freer ST, Rose PW. Complexity and simplicity of ligand-macromolecule interactions: the energy landscape perspective. Curr Opin Struct Biol 2002; 12: 197-203.
22. Carlson HA, McCammon JA. Accommodating protein flexibility in computational drug design. Mol Pharmacol 2000; 57: 213-8.
23. Holtje HD, Kier LB. Sweet taste receptor studies using model interaction energy calculations. J Pharm Sci 1974; 63: 1722-5.
24. Kier LB, Aldrich HS. A theoretical study of receptor site models for trimethylammonium group interaction. J Theor Biol 1974; 46: 529-41.
25. Kuntz ID, Blaney JM, Oatley SJ, Langridge R, Ferrin TE. A geometric approach to macromolecule-ligand interactions. J Mol Biol 1982; 161: 269-88.
26. Rarey M, Kramer B, Lengauer T, Klebe G. A fast flexible docking method using an incremental construction algorithm. J Mol Biol 1996; 261: 470-89.
27. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, et al. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 1998; 19: 1639-62.
28. Gane PJ, Dean PM. Recent advances in structure-based rational drug design. Curr Opin Struct Biol 2000; 10: 401-4.
29. Klebe G. Recent developments in structure-based drug design. J Mol Med 2000; 78: 269-81.
30. Muegge I, Rarey M. Small Molecule Docking and Scoring. Rev Comp Chem 2001; 17: 1-60.
31. Shoichet BK, McGovern SL, Wei B, Irwin JJ. Lead discovery using molecular docking. Curr Opin Chem Biol 2002; 6: 439-46.
32. Halperin I, Ma B, Wolfson H, Nussinov R. Principles of docking: An overview of search algorithms and a guide to scoring functions. Proteins 2002; 47: 409-43.
33. Carlson HA. Protein flexibility and drug design: how to hit a moving target. Curr Opin Chem Biol 2002; 6: 447-52.
34. Carlson HA. Protein Flexibility is an Important Component of Structure-Based Drug Discovery. Curr Pharm Des 2002; 8: 1571-8.
35. Jiang F, Kim SH. "Soft docking": matching of molecular surface cubes. J Mol Biol 1991; 219: 79-102.
36. Schnecke V, Swanson CA, Getzoff ED, Tainer JA, Kuhn LA. Screening a peptidyl database for potential ligands to proteins with side-chain flexibility. Proteins 1998; 33: 74-87.
37. Apostolakis J, Pluckthun A, Caflisch A. Docking small ligands in flexible binding sites. J Comput Chem 1998; 19: 21-37.
38. MacKerell AD, Bashford D, Bellot M, Karplus M. All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B 1998; 102: 3586-616.
39. Cornell WD, Cieplak P, Bayly CI, Gould IR, Merz KM, Ferguson DM, et al. A second generation force field for the simulation of proteins and nucleic acids. J Am Chem Soc 1995; 117: 5179-97.
40. Tuffery P, Etchebest C, Hazout S, Lavery R. A new approach to the rapid determination of protein side chain conformations. J Biomol Struct Dyn 1991; 8: 1267-89.
41. Lovell SC, Word JM, Richardson JS, Richardson DC. The penultimate rotamer library. Proteins 2000; 40: 389-408.
42. Dunbrack R. Rotamer Libraries in the 21(st) Century. Curr Opin Struct Biol 2002; 12: 431.
43. Leach AR. Ligand docking to proteins with discrete side-chain flexibility. J Mol Biol 1994; 235: 345-56.
44. Desmet J, DeMaeyer M, Hazes B, Lasters I. The dead-end elimination theorem and its use in protein side-chain positioning. Nature 1992; 356: 539-42.
45. Hart PE, N.J. N, Raphael B. A formal basis for the heuristic determination of minimum cost paths. IEEE T Syst Sci Cyb 1968; 4: 100-14.
46. Leach AR, Lemon AP. Exploring the conformational space of protein side chains using dead-end elimination and the A* algorithm. Proteins 1998; 33: 227-39.
47. Schaffer L, Verkhivker GM. Predicting structural effects in HIV-1 protease mutant complexes with flexible ligand docking and protein side-chain optimization. Proteins 1998; 33: 295-310.
48. Althaus E, Kohlbacher O, Lenhof HP, Muller P. A combinatorial approach to protein docking with flexible side chains. J Comput Biol 2002; 9: 597-612.
49. 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: 727-48.
50. Anderson AC, O'Neil RH, Surti TS, Stroud RM. Approaches to solving the rigid receptor problem by identifying a minimal set of flexible residues during ligand docking. Chem Biol 2001; 8: 445-57.
51. Kairys V, Gilson MK. Enhanced docking with the mining minima optimizer: acceleration and side-chain flexibility. J Comput Chem 2002; 23: 1656-70.
52. David L, Luo R, Gilson MK. Ligand-receptor docking with the Mining Minima optimizer. J Comput Aid Mol Des 2001; 15: 157-71.
53. Totrov M, Abagyan R. Flexible protein-ligand docking by global energy optimization in internal coordinates. Proteins 1997; Suppl: 215-20.
54. Katritch V, Totrov M, Abagyan R. ICFF: A new method to incorporate implicit flexibility into an internal coordinate force field. J Comput Chem 2003; 24: 254-65.
55. Noguti T, Go N. Structural basis of hierarchical multiple substates of a protein. I: Introduction. Proteins 1989; 5: 97-103.
56. Frauenfelder H, Sligar SG, Wolynes PG. The energy landscapes and motions of proteins. Science 1991; 254: 1598-603.
57. Kitao A, Hayward S, Go N. Energy landscape of a native protein: jumping-among-minima model. Proteins 1998; 33: 496-517.
58. Rich DH, Bursavich MG, Estiarte MA. Discovery of nonpeptide, peptidomimetic peptidase inhibitors that target alternate enzyme active site conformations. Biopolymers 2002; 66: 115-25.
59. Clarage JB, Romo T, Andrews BK, Pettitt BM, Phillips GN, Jr. A sampling problem in molecular dynamics simulations of macromolecules. Proc Natl Acad Sci USA 1995; 92: 3288-92.
60. Philippopoulos M, Lim C. Exploring the dynamic information content of a protein NMR structure: comparison of a molecular dynamics simulation with the NMR and X-ray structures of Escherichia coli ribonuclease HI. Proteins 1999; 36: 87-110.
61. Karplus M, McCammon JA. Molecular dynamics simulations of biomolecules. Nat Struct Biol 2002; 9: 646-52.
62. Pang YP, Kozikowski AP. Prediction of the binding sites of huperzine A in acetylcholinesterase by docking studies. J Comput Aid Mol Des 1994; 8: 669-81.
63. Lin JH, Perryman AL, Schames JR, McCammon JA. Computational drug design accommodating receptor flexibility: the rellaxed complex scheme. J Am Chem Soc 2002; 124: 5632-3.
64. Kua J, Zhang Y, McCammon JA. Studying enzyme binding specificity in acetylcholinesterase using a combined molecular dynamics and multiple docking approach. J Am Chem Soc 2002; 124: 8260-7.
65. Knegtel RM, Kuntz ID, Oshiro CM. Molecular docking to ensembles of protein structures. J Mol Biol 1997; 266: 424-40.
66. Sudbeck EA, Mao C, Vig R, Venkatachalam TK, Tuel-Ahlgren L, Uckun FM. Structure-based design of novel dihydroalkoxybenzyloxopyrimidine derivatives as potent nonnucleoside inhibitors of the human immunodeficiency virus reverse transcriptase. Antimicrob Agents Ch 1998; 42: 3225-33.
67. Bouzida D, Rejto PA, Arthurs S, Colson AB, Freer ST, Gehlhaar DK, et al. Computer simulations of ligand-protein binding with ensembles of protein conformations: A Monte Carlo study of HIV-1 protease binding energy landscapes. Int J Quantum Chem 1999; 72: 73-84.
68. 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: 247-57, 302-4.
69. Osterberg F, Morris GM, Sanner MF, Olson AJ, Goodsell DS. Automated docking to multiple target structures: incorporation of protein mobility and structural water heterogeneity in AutoDock. Proteins 2002; 46: 34-40.
70. Kastenholz MA, Pastor M, Cruciani G, Haaksma EE, Fox T. GRID/CPCA: a new computational tool to design selective ligands. J Med Chem 2000; 43: 3033-44.
71. Pastor M, Cruciani G. A novel strategy for improving ligand selectivity in receptor-based drug design. J Med Chem 1995; 38: 4637-47.
72. Claussen H, Buning C, Rarey M, Lengauer T. FlexE: efficient molecular docking considering protein structure variations. J Mol Biol 2001; 308: 377-95.
73. Moreno E, Leon K. Geometric and chemical patterns of interaction in protein-ligand complexes and their application in docking. Proteins 2002; 47: 1-13.
74. Bolin JT, Filman DJ, Matthews DA, Hamlin RC, Kraut J. Crystal structures of Escherichia coli and Lactobacillus casei dihydrofolate reductase refined at 1.7 A resolution, I. General features and binding of methotrexate. J Biol Chem 1982; 257: 13650-62.
75. DesJarlais RL, Sheridan RP, Seibel GL, Dixon JS, Kuntz ID, Venkataraghavan R. Using shape complementarity as an initial screen in designing ligands for a receptor binding site of known three-dimensional structure. J Med Chem 1988; 31: 722-9.
76. Oshiro CM, Kuntz ID. Characterization of receptors with a new negative image: use in molecular docking and lead optimization. Proteins 1998; 30: 321-36.
77. Carlson HA, Masukawa KM, McCammon JA. Method for Including the Dynamic Fluctuations of a Protein in Computer-Aided Drug Design. J Chem Inf Comput Sci 1999; 103: 10213-9.
78. Carlson HA, Masukawa KM, Rubins K, Bushman FD, Jorgensen WL, Lins RD, et al. Developing a dynamic pharmacophore model for HIV-1 integrase. J Med Chem 2000; 43: 2100-14.
79. Stultz CM, Karplus M. MCSS functionality maps for a flexible protein. Proteins 1999; 37: 512-29.
80. Di Nola A, Roccatano D, Berendsen HJ. Molecular dynamics simulation of the docking of substrates to proteins. Proteins 1994; 19: 174-82.
81. Mangoni M, Roccatano D, Di Nola A. Docking of flexible ligands to flexible receptors in solution by molecular dynamics simulation. Proteins 1999; 35: 153-62.
82. Luty BA, Wasserman R, Stouten P, Hodge CN, Zacharias M, McCammon JA. A Molecular Mechanics/Grid Method for Evaluation of Ligand-Receptor Interactions. J Comput Chem 1995; 16: 454-64.
83. Wasserman ZR, Hodge CN. Fitting an inhibitor into the active site of thermolysin: a molecular dynamics case study. Proteins 1996; 24: 227-37.
84. Given JA, Gilson MK. A hierarchical method for generating low-energy conformers of a protein-ligand complex. Proteins 1998; 33: 475-95.
85. Nakajima N, Higoa J, Kiderab A, Nakamura H. Flexible docking of a ligand peptide to a receptor protein by multicarionical molecular dynamics simulation. Chem Phys Lett 1997; 278: 297-301.
86. Nakajima N, Nakamura H, Kidera A. Multicanonical Ensemble Generated by Molecular Dynamics Simulation for Enhanced Conformational Sampling of Peptides. J Phys Chem B 1997; 101: 817-24.
87. Berg BA, Neuhaus T. Multicanonical ensemble: A new approach to simulate first-order phase transitions. Phys Rev Lett 1992; 68: 9-12.
88. Pak Y, Wang C. Application of a Molecular Dynamics Simulation Method with a Generalized Effective Potential to the Flexible Molecular Docking Problems. J Phys Chem B 2000; 104: 354-9.
89. Zhu J, Fan H, Liu H, Shi Y. Structure-based ligand design for flexible proteins: application of new F-DycoBlock. J Comput Aid Mol Des 2001; 15: 979-96.
90. Caflisch A, Fischer S, Karplus M. Docking by Monte Carlo Minimization with a Solvation Correction: Application to an FKBP-Substrate Complex. J Comput Chem 1997; 18: 723-43.
91. Trosset JY, Scheraga HA. Flexible docking simulations: scaled collective variable Monte Carlo minimization approach using Bezier splines, and comparison with a standard Monte Carlo algorithm. J Comput Chem 1999; 20: 244-52.
92. Noguti T, Go N. Efficient Monte Carlo method for simulation of fluctuating conformations of native proteins. Biopolymers 1985; 24: 527-46.
93. Trosset JY, Scheraga HA. Reaching the global minimum in docking simulations: a Monte Carlo energy minimization approach using Bezier splines. Proc Natl Acad Sci USA 1998; 95: 8011-5.
94. Trosset JY, Scheraga HA. PRODOCK: Software Package for Protein Modeling and Docking. J Comput Chem 1999; 20: 412-27.
95. Verkhivker GM, Rejto PA, Bouzida D, Arthurs S, Colson AB, Freer ST, et al. Parallel simulated tempering dynamics of ligand-protein binding with ensembles of protein conformations. Chem Phys Lett 2001; 337: 181-9.
96. 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: 607-17.
97. Levy RM, Karplus M. Vibrational Approach to the Dynamics of an alpha-Helix. Biopolymers 1979; 18: 2465-95.
98. Go N, Noguti T, Nishikawa T. Dynamics of a small globular protein in terms of low-frequency vibrational modes. Proc Natl Acad Sci USA 1983; 80: 3696-700.
99. Levitt M, Sander C, Stern PS. Protein normal-mode dynamics: trypsin inhibitor, crambin, ribonuclease and lysozyme. J Mol Biol 1985; 181: 423-47.
100. Zacharias M, Sklenar H. Harmonic Modes as Variables to Approximately Account for Receptor Flexibility in Ligand-Receptor Docking Simulations: Application to DNA Minor Groove Ligand Complex. J Comput Chem 1999; 20: 287-300.
101. Keseru GM, Kolossvary I. Fully flexible low-mode docking: application to induced fit in HIV integrase. J Am Chem Soc 2001; 123: 12708-9.
102. Kolossvary I, Guida WC. Low-Mode Conformational Search Elucidated: Application to C39H80 and Flexible Docking of 9-Deazaguanine Inhibitors into PNP. J Comput Chem 1999; 20: 1671-84.
103. Kolossvary I, Keseru GM. Hessian-Free Low-Mode Conformational Search for Large-Scale Protein Loop Optimization: Application to c-jun N-Terminal Kinase JNK3. J Comput Chem 2001; 22: 21-30.
104. Garcia AE. Large-amplitude nonlinear motions in proteins. Phys Rev Lett 1992; 68: 2696-9.
105. Romo TD, Clarage JB, Sorensen DC, Phillips GN, Jr. Automatic identification of discrete substates in proteins: singular value decomposition analysis of time-averaged crystallographic refinements. Proteins 1995; 22: 311-21.
106. Caves LS, Evanseck JD, Karplus M. Locally accessible conformations of proteins: multiple molecular dynamics simulations of crambin. Protein Sci 1998; 7: 649-66.
107. Kitao A, Go N. Investigating protein dynamics in collective coordinate space. Curr Opin Struct Biol 1999; 9: 164-9.
108. Amadei A, Linssen AB, Berendsen HJ. Essential dynamics of proteins. Proteins 1993; 17: 412-25.
109. Amadei A, Linssen AB, de Groot BL, van Aalten DM, Berendsen HJ. An efficient method for sampling the essential subspace of proteins. J Biomol Struct Dyn 1996; 13: 615-25.
110. Abseher R, Nilges M. Efficient sampling in collective coordinate space. Proteins 2000; 39: 82-8.
111. de Groot BL, Amadei A, van Aalten DM, Berendsen HJ. Toward an exhaustive sampling of the configurational spaces of the two forms of the peptide hormone guanylin. J Biomol Struct Dyn 1996; 13: 741-51.
112. de Groot BL, Amadei A, Scheek RM, van Nuland NA, Berendsen HJ. An extended sampling of the configurational space of HPr from E. coli. Proteins 1996; 26: 314-22.
113. Teodoro ML, Phillips GN, Jr., Kavraki LE. Understanding Protein Flexibility Through Dimensionality Reduction. J Comput Biol 2003; to appear.
114. Sandak B, Nussinov R, Wolfson HJ. An automated computer vision and robotics-based technique for 3-D flexible biomolecular docking and matching. Comput Appl Biosci 1905; 11: 87-99.
115. Sandak B, Nussinov R, Wolfson HJ. A method for biomolecular structural recognition and docking allowing conformational flexibility. J Comput Biol 1998; 5: 631-54.
116. Sandak B, Wolfson HJ, Nussinov R. Flexible docking allowing induced fit in proteins: insights from an open to closed conformational isomers. Proteins 1998; 32: 159-74.
117. Jacobs DJ, Rader AJ, Kuhn LA, Thorpe MF. Protein flexibility predictions using graph theory. Proteins 2001; 44: 150-65.
118. Raymer ML, Sanschagrin PC, Punch WF, Venkataraman S, Goodman ED, Kuhn LA. Predicting conserved water-mediated and polar ligand interactions in proteins using a K-nearest-neighbors genetic algorithm. J Mol Biol 1997; 265: 445-64.
119. Rarey M, Kramer B, Lengauer T. The particle concept: placing discrete water molecules during protein-ligand docking predictions. Proteins 1999; 34: 17-28.
120. Majeux N, Scarsi M, Apostolakis J, Ehrhardt C, Caflisch A. Exhaustive docking of molecular fragments with electrostatic solvation. Proteins 1999; 37: 88-105.
121. Shoichet BK, Leach AR, Kuntz ID. Ligand solvation in molecular docking. Proteins 1999; 34: 4-16.
122. Zhang LY, Gallicchio E, Friesner RA, Levy RM. Solvent Models for Protein-Ligand Binding: Comparison of Implicit Solvent Poisson and Surface Generalized Born Models with Explicit Solvent Simulations. J Comput Chem 2001; 22: 591-607.
123. Kollman PA. Free energy calculations: Applications to chemical and biochemical phenomena. Chem Rev 1993; 93: 2395-417.
124. Ajay, Murcko MA. Computational methods to predict binding free energy in ligand-receptor complexes. J Med Chem 1995; 38: 4953-67.
125. Oprea TI, Marshall GR. Receptor-based prediction of binding affinities. Perpect Drug Discov 1998; 9-11: 35-61.
126. Holloway MK. A priori prediction of ligand affinity by energy minimization. Perpect Drug Discov 1998; 9-11: 63-84.
127. Vieth M, Hirst JD, Kolinski A, Brooks CLI. Assessing energy functions for flexible docking. J Comput Chem 1998; 19: 1612-22.
128. Tame JR. Scoring functions: a view from the bench. J Comput Aid Mol Des 1999; 13: 99-108.
129. Charifson PS, Corkery JJ, Murcko MA, Walters WP. Consensus scoring: A method for obtaining improved hit rates from docking databases of three-dimensional structures into proteins. J Med Chem 1999; 42: 5100-9.
130. Carlson HA. Protein flexibility is an important component of structure-based drug discovery. Curr Pharm Des 2002; 8(17): 1571-8.
131. Mason JS, Good AC, Martin EJ. 3-D pharmacophores in drug discovery. Curr Pharm Des 2001; 7(7): 567-97.
132. Mekenyan O. Dynamic QSAR techniques: applications in drug design and toxicology. Curr Pharm Des 2002; 8(17): 1605-21.