Docking structures

Genetic algorithms can also be used to perform molecular docking [Judson et d. 1994 Jont et d. 1995b Oshiro et d. 1995]. Each chromosome codes not only for the internal conform tion of the ligand as described in Section 9.9.1 but also for the orientation of the ligand withi the receptor site. Both the orientation and the internal conformation will thus vary as th populations evolve. The score of each docked structure within the site acts as the fitnes function used to select the individuals for the next iteration. 

Fig. 3 The SAR by NMR approach. Example of a small bidentate molecule designed using this approach. The example shown is for the design of a potent inhibitors of the matrix metalloproteinase MMP3. (a) Docked structures of the identified fragment leads are shown with cyan carbons, whereas the linked compound is shown with green carbon atoms. All structures were experimentally determined by NMR. (b) Chemical structures (and in vitro potencies) of the fragment leads and subsequent high-affinity linked compounds. Adapted from [7]...

CPI Tallies Dock Structure Losses, Chemical Week, Mar. 1, 1969, p. 12. 

Shown below are snapshots of structures from our simulations of native RT with Sustiva and nevirapine. No crystal structure had been reported for RT with Sustiva when the calculations were performed however, confidence in the computed structure comes from the quantitative accord for the inhibition penalties and because Matador yielded docked structures for nevirapine, MKC-442, and 9-C1-TIBO that are virtually identical to the crystal structures.57 Sustiva hydrogen bonds with the backbone of K101, as do MKC-442 and 9-chloro-TIBO, and it has hydrophobic interactions in the Y181-Y188 pocket, also typical of NNRTIs. 

Fig. 8. DNQX docked into the binding pocket of iGluR2 using Glide (21). The experimentally observed structure is shown in magenta and the atoms of the docked structure are type-coded.

In conclusion, using high-quality STD-NMR data on UDP-Gal weakly binding to 34 GalTl, we demonstrated that it is possible to refine the crystal structure (or any computer-docked structure in the proper orientation that serves as the starting structure) to obtain a global-minimum conformation for the bound ligand in solution. 

The Guy open conformation model docked structure was minimized in vacuo followed by a 1-ns molecular dynamics simulation of the complex embedded in a phosphatidylethanolamine (POPE) lipid bilayer. Adjustments were made to the model, and simulations were repeated so that very little movement occurred during the hnal iterations. Similar methods were used to dock the two domains in transitional and resting states. However, these results are more tenuous as little experimental data is available. In particular, the position of the S4-S5 linker and its role in opening and closing the pore are uncertain. The supplemental movie accompanying reference 36 illustrates the open-to-close-to-open cycle resulting from the simulations. 

Molecular docking (structure-based virtual screening) on the basis of a target protein structure, ligand molecules that bind to the active site of the target are searched for. 

Key Words CYP P450 cytochrome P450 docking structure-based drug discovery pharmacophore QSAR homology models databases computational models ADME/T. 

Energies of the Components of Docked Structures and of Binding of CDNB on GST-pi Polymorphs3... 

Sun, Y., Ewing, T.J.A., Skillman, A.G. and Kuntz, I.D. Combinatorial DOCK Structure-based Combinatorial Docking and Library Design, J. Comput.-AidedMol. Des., 1998, in press. 

Structural class. If 50% of the docked structures belong to a single chemical class, it is probably uimecessary to test all of them. 

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