In silico docking

The Role and Application of In Silico Docking in Chemical Genomics Research... 

Key Words In silico docking AutoDock FlexX GOLD virtual screening automated docking molecular docking. 

This chapter aims to present a very practical description of how to set up in silico docking experiments. Many problems and pitfalls that can be encountered during these experiments will be discussed. Because a thorough discussion of the theoretical background of the algorithms is beyond the scope of this chapter, references to important papers describing fundamental aspects are specifically mentioned in the text. 

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]. 

Lee Y et al (2009) Identification of compounds exhibiting inhibitory activity toward the Pseudomonas tolaasii toxin tolaasin I using in silico docking calculations, NMR binding assays, and in vitro hemolytic activity assays. Bioorg Med Chem Lett 19(15) 4321 324... 

Fig. 4 In silico docking studies obtained with fiexibie docking (Giide software package ) to the FimH-CRD (PDB iD 4X08) top-scored binding modes of (A) 44 (Tabie 1, entry 34) and (B) 46 (entry 38).

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