Docking

Description

Docking is a modeling process in which the interactions between molecules are examined. Docking algorithms could be applied to interactions between macromolecules (e.g., protein-protein or protein-DNA), but currently they are applied most often to small molecule-macromolecule interactions, as in drug design.

Preparation for docking involves the modeling and experimental techniques we have discussed earlier in the course. For example, the structure of the macromolecule, which we will refer to as the receptor, must be determined. Ideally, we will have structural information from X-ray diffraction or NMR, though a good homology model also could be used. The structure of the small molecule, the ligand, also is required. A model-built structure may be used, though extensive conformational searching should be done. Docking of several conformers of the ligand with the receptor may be advisable.

Docking can proceed after the structures are available. Various docking algorithms have been described; we have available the DOCK program from Kuntz's group. Also provided at their Web site is a description of the DOCK algorithm. DOCK is based on a sphere matching procedure and allows partial ligand flexibility. Another docking program is AutoDock. It applies simulated annealing to the docking process, allowing several torsional degrees of freedom in a flexible ligand to be searched. In addition, an automated docking algorithm, FlexX, is currently available for use over the WWW for free.

Once a collection of ligand-receptor complexes has been identified via docking, their relative stabilities can be evaluated using molecular dynamics and their binding affinities, using free energy simulations.

Printed References

Richards, F.M. (1977) Areas, Volumes, Packing, and Protein Structure. Ann. Rev. Biophys. Bioeng. 6, 151-176.

Kuntz, I.D., Blaney, J.M., Oatley, S.J., Langridge, R., and Ferrin, T.E. (1982) A Geometric Approach to Macromolecule-Ligand Interactions. J. Mol. Biol. 161, 269-288.

Kuntz, I.D. (1992) Structure-Based Strategies for Drug Design and Discovery. Science 257, 1078-1082.

Meng, E.C., Shoichet, B.K., and Kuntz, I.D. (1992) Automated Docking with Grid-Based Energy Evaluation. J. Comput. Chem. 13, 505-524.

Shoichet, B.K., Bodian, D.L., and Kuntz, I.D. (1992) Molecular Docking Using Shape Descriptors. J. Comput. Chem. 13, 380-397.

Shoichet, B.K., Stroud, R.M., Santi, D.V., Kuntz, I.D., and Perry, K.M. (1993) Structure-Based Discovery of Inhibitors of Thymidylate Synthase. Science 259, 1445-1450.

Kuntz, I.D., Meng, E.C., and Shoichet, B.K. (1994) Structure-Based Molecular Design. Acct. Chem. Res. 27, 117-123.

Goodsell, D.S., Morris, G.M., and Olson, A.J. (1996) Automated Docking of Flexible Ligands: Applications of AutoDock. J. Mol. Recog. 9, 1-5.

Rarey, M., Kramer, B., Lengauer, T., and Klebe, G. (1996) A Fast Flexible Docking Method Using an Incremental Construction Algorithm. J. Mol. Biol. 261, 470-489.