Docking predictions

Rarey, M., Kramer, B., and Lengauer, T. (1999) The particle concept placing discrete water molecules during protein-ligand docking predictions. Proteins 34,17-28. 

The Particle Concept Placing Discrete Water Molecules During Protein-Ligand Docking Predictions. 

If a three-dimensional structure of the PTP is available, in silico docking can be utilized to model and dock the inhibitor into the active site (Fig. 5). The docking can then be verified by mutagenesis studies, in which specific amino acids that the docking predicted to interact with the inhibitor are mutated to alanine. Inhibitory activity of the compound is then measured with the mutant protein and is expected to be lower than with the wild-type protein (Fig. 4c). Finally, biophysical binding studies, such as isothermal titration calorimetry (ITC) [33] or ThermoFluor [34] may further aid in prioritizing compounds for cell-based assays and high-resolution structural analysis. 

In a recent study, in silico docking predictions were used to evaluate interactions of 20 commonly used cancer drugs with CYP2D6. The results obtained led to the identification of a new oxidative metabolite of metoclopramide [119,128], The formation of this in silico predicted metabolite was later confirmed by LC-MS following incubation of metoclopramide with HLM and recombinant CYP2D6 [119]. 

V. Sobolev, T. M. Moallem, R. C. Wade, G. Vriend, and M. Edelman. Casp2 molecular docking predictions with the ligin software. PROTEINS Structure, Function and Genetics, Suppl. 1 1(1) 210—214, 1997. 

Sobolev, V, Moallem, T.M., Wade, R.C., Vriend, G., and Edelman, M. (1997) CASP2 molecular docking prediction with the LIGIN software. Proteins, 29 (Suppl. 1), 210-214. 

M. Rarey, B. Kramer, and T. Lengauei Proteins Struct., Pune., Genet., 34, 17 (1999). The Particle Concept Placing Discrete Water Molecules During Protein-Ligand Docking Predictions. 

Many of the techniques described previously for structure prediction of macromolecules and docking predictions can be applied to the conformation analysis of small molecules with a view to energy minimization or constraint satisfaction. (See Conformational Analysis 1 Conformational Analysis 2 Conformational Analysis 3 Conformational Search Linear Chains Conformational Search Medium-sized Molecules and Conformational Search Proteins.)... 

In addition to protein-protein complexes, one CAPRI target was a protein-RNA complex, and three were homo-oligomers. Target T33, the protein-RNA complex, contained a segment of ribosomal RNA, and the predictors were given coordinates taken from an X-ray structure of the ribosome. Because the RNA of the target complex has a different sequence and a very different conformation, docking predictions were expected to fail. They did. 

Figure 5 A summary of the results of the CAPRI predictions submissions made by predictor groups. For each target offered for docking prediction since CAPRI started in 2001, bars represent the cumulative percentages of submitted models evaluated as high-, medium-, or acceptable quality. The remainder comprises incorrect models and models disqualified because of an excess of clashes or low-sequence identity. With targets T27 and T48-49, two possible modes of assembly had to be considered when assessing the models (see Figure 7). Detailed results of the assessment are reported in Refs. 63, 64, 105,162, and 163.

I. A. Vakser, Biopolymers, 39, 455-464 (1996). Low-Resolution Docking Prediction of Complexes for Underdetermined Structures. 

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