Docking simulation

If structural information of the protein target is available, e.g., a crystal structure, in silico screening of huge virtual compound libraries can be conducted by the use of docking simulations. Based on identified primary hits, structural variations of the ligand can be evaluated by computational modeling of the ligand-protein complex. 

Anzini M, Canullo L, Braile C, et ah Synthesis, biological evaluation, and receptor docking simulations of 2-[(acylamino)ethyl]-1,4-benzodiazepines as kappa-opioid receptor agonists endowed with antinociceptive and antiamnesic activity. J Med Chem 46 3833-3864, 2003... 

Structural properties of both AFA-PLN and WT-PLN bound to SER-CAla after reconstitution in a functional lipid bilayer environment were examined by 13C solid-state NMR.241 Chemical-shift assignments in all domains of AFA-PLN provide direct evidence for the presence of two terminal ot-helices connected by a linker region of reduced structural order that differs from previous findings on free PLN. A combination of the spectroscopic data with biophysical and biochemical data using flexible protein-protein docking simulations provides a structural basis for understanding the interaction between PLN and SERCala.244 Using a... 

II. Docking simulation methods These are slower than the matching one, study the ligand outside the protein and randomly explore translations, orientations and conformations until an ideal site is found. 

L. (1996) Synthesis, biological evaluation, and quantitative receptor docking simulations of 2-[(acylamino) ethyl]-l,4-benzodiazepines as novel tifluadom-like ligands with high affinity and selectivity for kappa-opioid receptors. Journal of Medicinal Chemistry, 39, 860-872. 

Using information about the 3D shape of a protein receptor active site, which is derived from X-ray crystallography or NMR, ligands from the virtual library can be selected and fitted into the site. This is a modeling process known as docking simulation (Fig. 3.6). 

Docking simulation is distinct from wet laboratory chemistry, where chemical reactions are performed using real rather than virtual compounds. The docking approach is more cost effective and efficient than the conventional chemical synthesis route. It allows a large database of virtual compounds to be screened and matched up with the binding site of the targeted protein. 

Figure 3.6 Docking simulations. (Source Liu H, Huang X, Shen J, et al. Inhibitory mode of 1,5-diarylpyrazole derivatives against cyclooxygenase-2 and cyclooxygenase-1 molecular docking and 3D QSAR analyses, Journal of Medicinal Chemistry 45 4816-4827 (2002). Used with permission.)...

Trosset J-Y, Scheraga HA (1999) Flexible docking simulations scaled collective variable Monte Carlo minimization approach using Bezier splines, and comparison with a standard Monte Carlo algorithm. J Comp Chem 20 244-252... 

Fig. 10.4. (a) Crystal structure of gp11 p-HSD1 complex with Reactant A which was used as defining ligand in docking simulations, (b) Adamantyl amide core structure used in fixed anchor docking. 

Export the resulting 279 predicted property compliant virtual products as a structure file in SDF format for docking simulations. Our objective was to narrow down the products to 88 compounds to fill a single screening plate at Pfizer. 

The putative binding model of arylthioindoles described above was further confirmed by docking simulations on a third series of compounds synthesized by the same group [43],... 

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