Docking

The program FLAP fits ligand molecules into a set of GRID MIFs of a protein structure. Thus FLAP can be used as docking program, which uses all the GRID force fields options and capabilities. 

In atom-type color is reported the X-ray crystallographic structure as a comparison. 

The final output of the docking procedure is a set of solutions ranked according to the corresponding scoring function values, each defined by the 3D coordinates of its atoms and expressed as a PDB file. 

Using a comparative study on the docking programs DOCK, FlexX and GOLD, performed by Paul and Rognan [28], we could compare 83 ligand-protein complexes out of the whole dataset of 230 complexes. 

Defining as best pose a well-docked solution with the value of its RMSD to the X-ray 3D structure lower than 2.00 A, the best pose obtained by GLUE was among its three first solutions for 69 out of 83 cases (83%), whereas DOCK, FlexX and GOLD obtained 18 (22%), 20 (24%), 20 (24%) respectively (Fig. 4.5). 

Molecular mechanics also enables the medicinal chemist to calculate the binding energy of a ligand. This is the energy lost when the ligand binds to its target site, that is 

All the quantities on the right hand side of the equation may be calculated using molecular mechanics force fields. However, it should be remembered that in many cases the binding of a drug to its target should be weak, because in most cases it has to be able to leave the target after it has activated that site. 

However, it is normally assumed that the conformers that bind to target sites will be those with a minimum potential energy. Since molecules may have large numbers of such metastable conformers a number of techniques, such as the Metropolis Monte Carlo method and comparative molecular field analysis (CoMFA), have been developed to determine the effect of conformational changes on the effectiveness of docking procedures. 

Docking proceedures have also been adapted to design possible leads. The computer is used to fit suitable structural fragments into the docking area. These fragments are joined to make molecules that fit the docking site. This procedure is referred to as De novo design. 

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Figure A3.10.2 The influence of corrosion (C) and marine fouling (F) on the perfonnance of a steel ship dry docked amuially for cleaning and painting [5].

The cross relation has proven valuable to estimate ET rates of interest from data tliat might be more readily available for individual reaction partners. Simple application of tire cross-relation is, of course, limited if tire electronic coupling interactions associated with tire self exchange processes are drastically different from tliose for tire cross reaction. This is a particular concern in protein/protein ET reactions where tire coupling may vary drastically as a function of docking geometry. 

Strynadka et al., 1996] Strynadka, N., Eisenstein, M., Katchalski-Katzir, E., Shoichet, B., Kuntz, I., Abagyan, R., Totrov, M., Janin, J., Cherflls, J., Zimmerman, F., Olson, A., Duncan, B., Rao, M., Jackson, R., Sternberg, M., and James, M. Molecular docking programs successfully predict the binding of a /3-lactamase inhibitory protein to TEM-1 /3-lactamase. Nature Struct. Biol. 3 (1996) 233-239... 

Some aspects, such as the computer representation and manipulation of proteins and nucleic acids, could not be covered. Even the modeling of the interactions of small molecules with proteins, as dealt with in docking software or software for de novo design could not be included in the Textbook, although chapters in the Handbook do treat these subjects. 

The interpretation of molecular surfaces is particularly important wherever molecular interactions, reactions, and properties play a dominant role, such as in drug design or in docking c.xpcrimcnts. 

Protein structure know 11 dt novo design, receptor-based 3D searching stnjcture-based design, docking... 

Figure 10.4-5. Different strategies to design a ligand in structure-based drug design docking (left), building (center), and linking (right),...

An overview of docking programs is given in Tabic 10.4-3. Depending on the way the conformational flexibility of the ligand is treated, docking can be either rigid or flexible. 

Table 10.4 3. Common docking tools for virtual screening.

Dock [59] incremental build force field or contact score... 

The calculation of the binding affinity with con.sidcration of all tbc.se effects for virtual screening is not possible. In order to circumvent thus difficulty, scoring functions arc used instead, c.g., the Liidi scoring function [80, or consensus scoring functions derived from FlevX score, DOCK score, GOLD score, ChemScore, or PMF score [81 ]. 

Hypoxanthme-guanine-xanthiiie phosphoribosyl transferase Dock 88... 

Zhang and co-workers worked on the structure-based, computer-assisted search for low molecular weight, non-peptidic protein tyrosine phosphate IB (PTPIB) inhibitors, also using the DOCK methodology [89], They identified several potent and selective PTPIB inhibitors by saeening the ACD. 

Docking also provided insight into the 3D hydrophobic requirements for binding of nonpeptide molecules in the SH2 domain of ppGOsrc at ARIAD Pharmaceuticals [92]. 

Dock two different m o lecu Ics by restraining in term o Iccu lar (in Icratom icf distan ces. 

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