Two-stage method for protein-ligand docking.

A two-stage method for the computational prediction of the structure of protein-ligand complexes is proposed. Given an experimentally determined structure of the protein, in the first stage a large number of plausible ligand conformations is generated using the fast docking algorithm FlexX. In the second stage these conformations are minimized and reranked using a method based on a classical force field. The two-stage method is tested for 10 different protein-ligand complexes. For 9 of them experimentally determined structures are known. It turns out that the two-stage method strongly improves the predictive power as compared to that of the fast docking stage alone. The tenth case is a bona fide prediction of a complex of thrombin with a new inhibitor for which no experimentally determined structure is available so far.

[1]  J. Warwicker,et al.  Calculation of the electric potential in the active site cleft due to alpha-helix dipoles. , 1982, Journal of molecular biology.

[2]  Robert B. Hermann,et al.  Theory of hydrophobic bonding. II. Correlation of hydrocarbon solubility in water with solvent cavity surface area , 1972 .

[3]  Y. Konishi,et al.  Crystal structure of a peptidyl pyridinium methyl ketone inhibitor with thrombin. , 1995, Biochemistry.

[4]  P E Wright,et al.  Electrostatic calculations of side-chain pK(a) values in myoglobin and comparison with NMR data for histidines. , 1993, Biochemistry.

[5]  D. Banner,et al.  Crystallographic analysis at 3.0-A resolution of the binding to human thrombin of four active site-directed inhibitors. , 1994, The Journal of biological chemistry.

[6]  A. D. McLachlan,et al.  Solvation energy in protein folding and binding , 1986, Nature.

[7]  R. Harrison,et al.  Prediction of new serine proteinase inhibitors , 1994, Nature Structural Biology.

[8]  Daniel A. Gschwend,et al.  Orientational sampling and rigid-body minimization in molecular docking revisited: On-the-fly optimization and degeneracy removal , 1996, J. Comput. Aided Mol. Des..

[9]  H. Scheraga,et al.  Accessible surface areas as a measure of the thermodynamic parameters of hydration of peptides. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J M Blaney,et al.  A geometric approach to macromolecule-ligand interactions. , 1982, Journal of molecular biology.

[11]  D. E. Clark,et al.  Flexible docking using tabu search and an empirical estimate of binding affinity , 1998, Proteins.

[12]  A. N. Jain,et al.  Hammerhead: fast, fully automated docking of flexible ligands to protein binding sites. , 1996, Chemistry & biology.

[13]  Hans-Joachim Böhm,et al.  The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure , 1994, J. Comput. Aided Mol. Des..

[14]  G. Cohen,et al.  On the specificity of antibody/antigen interactions: phosphocholine binding to McPC603 and the correlation of three-dimensional structure and sequence data. , 1985, Annales de l'Institut Pasteur. Immunologie.

[15]  A. Edmundson,et al.  Local and transmitted conformational changes on complexation of an anti-sweetener Fab. , 1994, Journal of molecular biology.

[16]  J C Sacchettini,et al.  Escherichia coli-derived rat intestinal fatty acid binding protein with bound myristate at 1.5 A resolution and I-FABPArg106-->Gln with bound oleate at 1.74 A resolution. , 1994, The Journal of biological chemistry.

[17]  M J Sternberg,et al.  A continuum model for protein-protein interactions: application to the docking problem. , 1995, Journal of molecular biology.

[18]  S. Reissmann,et al.  New thrombin inhibitors based on D-cha-Pro-derivatives. , 1999, Journal of enzyme inhibition.

[19]  J. Stürzebecher,et al.  Cyclic amides of N alpha-arylsulfonylaminoacylated 4-amidinophenylalanine--tight binding inhibitors of thrombin. , 1983, Thrombosis research.

[20]  J. Springer,et al.  Structural analysis of inositol monophosphatase complexes with substrates. , 1994, Biochemistry.

[21]  J L Sussman,et al.  Protein Data Bank (PDB): database of three-dimensional structural information of biological macromolecules. , 1998, Acta crystallographica. Section D, Biological crystallography.

[22]  Barry Honig,et al.  Focusing of electric fields in the active site of Cu‐Zn superoxide dismutase: Effects of ionic strength and amino‐acid modification , 1986, Proteins.

[23]  J. Skehel,et al.  Refinement of the influenza virus hemagglutinin by simulated annealing. , 1991, Journal of molecular biology.

[24]  B. Honig,et al.  Classical electrostatics in biology and chemistry. , 1995, Science.

[25]  R. Freidinger,et al.  Design of highly potent noncovalent thrombin inhibitors that utilize a novel lipophilic binding pocket in the thrombin active site. , 1997, Journal of medicinal chemistry.

[26]  A. North,et al.  Pheromone binding to two rodent urinary proteins revealed by X-ray crystallography , 1992, Nature.

[27]  M. Karplus,et al.  pKa's of ionizable groups in proteins: atomic detail from a continuum electrostatic model. , 1990, Biochemistry.

[28]  T Lengauer,et al.  The particle concept: placing discrete water molecules during protein‐ligand docking predictions , 1999, Proteins.

[29]  J L Sussman,et al.  Protein Data Bank archives of three-dimensional macromolecular structures. , 1997, Methods in enzymology.

[30]  S. Pehrsson,et al.  Effects of Melagatran, a New Low-molecular-weight Thrombin Inhibitor, on Thrombin and Fibrinolytic Enzymes , 1998, Thrombosis and Haemostasis.

[31]  P Willett,et al.  Development and validation of a genetic algorithm for flexible docking. , 1997, Journal of molecular biology.

[32]  D. Goodsell,et al.  Automated docking of substrates to proteins by simulated annealing , 1990, Proteins.

[33]  Thomas Lengauer,et al.  Multiple automatic base selection: Protein–ligand docking based on incremental construction without manual intervention , 1997, J. Comput. Aided Mol. Des..

[34]  M. Karplus,et al.  CHARMM: A program for macromolecular energy, minimization, and dynamics calculations , 1983 .

[35]  A Wlodawer,et al.  Inhibitors of HIV-1 protease: a major success of structure-assisted drug design. , 1998, Annual review of biophysics and biomolecular structure.

[36]  M. Gelb,et al.  Crystal structure of bee-venom phospholipase A2 in a complex with a transition-state analogue , 1990, Science.