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Document Page 378 design such molecules on the basis of the trypanosomal TIM structure by a linked-fragment approach [57]. In that strategy small building blocks are designed to be complementary to the targeted surface of a protein. Such fragments can then be synthesized or purchased, tested for their effect on enzyme kinetics and for their binding mode by crystallography. Promising fragments are then linked together into larger molecules. The idea behind this stepwise approach is to obtain early experimental feedback in the drugdesign cycle. The crystallographic follow-up of our linked-fragment approach design for trypanosomal TIM was disappointing. Two designed fragments were soaked into a crystal of trypanosomal TIM, namely 4hydroxy-2-butanone and D-asparagine. Despite high concentrations of these molecules in the mother liquor, 220mM and 30 mM respectively, no convincing electron density could be seen in difference Fourier maps calculated between 10.0-2.8 Å [72]. Common to both molecules is that they are fairly polar, rather flexible, and were expected to displace crystallographically observed water molecules. Apparently, de novo design of tightly binding small ligands is far from trivial. We also tried to find new leads by a completely experimental approach. For that purpose the crystallographic cocktail soak (CCS) approach was developed. In this method cocktails of fine chemicals are soaked into a crystal in the hope of finding crystallographic evidence of binding for one of the molecules from the cocktail. The identification of such a molecule might not be clear immediately because several molecules in the cocktail might be compatible with the shape of the electron density, especially if the resolution is not very high. An outcome would be provided by a dichotomic approach (Figure 9), in which the crystallographic soaking experiment is repeated with ever smaller subcocktails of the original one. For example, if a ligand shows up from a cocktail soak of 32 compounds, a second experiment should be done with only half of the compounds. If the ligand fails to show up, one knows that it is one of the alternative 16 compounds. After at most six experiments the identity of the ligand is known. One might like to think of the CCS approach as the experimental analog of the computational methods in programs like GRID [73] or MCSS [74], but with thirty-two compounds at a time. Figure 9 Dichotomic search for unknown ligand from cocktail 1. The number of compounds in the sub cocktail is indicated by n, and the interpretation about the presence of compound X in the subcocktail is given as Y/?/N. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_378.html (1 of 2) [4/5/2004 5:39:46 PM]
Document Page 379 For trypanosomal TIM we experimented with three different cocktails of 32 compounds (Table 4). Molecules were chosen in such a way that they would be compatible, soluble, cheap, and as varied as possible. Each compound was present at a concentration of 1 mM. The final cocktail solutions were clear and devoid of precipitate. Since this was a pilot experiment both subcocktails were checked at each stage of the dichotomic strategy. Only the soak with cocktail 1 revealed electron density that could not be accounted for by water molecules, hereafter called peak X. The soaks with cocktails 2 and 3 led to featureless difference Fourier maps. The quality of the data and refinement can be inspected from Table 5, while Figure 9 illustrates the dichotomic search to identify peak X. An oxidized molecule of DTT, identified in the high-resolution structure of the native TIM crystals [24], served as an internal reference to judge the quality of the data and the noise level in the final difference Fourier maps. Peak X was found near His95 of the second subunit of the enzyme, i.e., the subunit where the flexible loop adopts the closed conformation in this crystal form. Its signal was somewhat weaker than that of DTT. The same density showed up when crystals were soaked with subcocktail 1B but not with 1A, narrowing down the list of potential ligands to sixteen compounds. However, the next round of the dichotomic search led to a problem that has not been solved thus far. Peaks of roughly the same shape as the original peak X appeared with both subcocktails 1BA and 1BB. Several strategies were followed to improved the quality of the maps. First, the model was further refined with all data while a bulk solvent scattering correction [75] was incorporated. Second, a variety of maps were calculated: (|F o|-|F c|) e iαc, (2|Fo|-|Fc|) eiαc, (3|Fo|-2|Fc|) eiαc and (|Fo|-|Fo,native|)eiαc. Third, all maps were SIGMAA-weighted [76]. Since the shape of peak X varied substantially between the different maps it can be tentatively concluded that peak X did not originate from the presence of a compound but was noise. The lesson of this experiment seems to be that the crystallographic cocktail soaking approach should only be tried when high- resolution data can be obtained, probably better than 1.8 Å resolution. B. Glyceraldehyde-3-Phosphate Dehydrogenase: Docking In order to discover new ligands that would block GAPDH of T. brucei by occupying the adenosine binding region we used the program DOCK [77], version 3.5. This program characterizes a binding site by filling it with a set of overlapping spheres. The centers of these generated spheres constitute an irregular grid, called a “graph” by mathematicians. Docking of a ligand then consists of matching subsets of ligand interatomic distances onto subsets of the receptor graph. Finally, the quality of the fit between a docked ligand and the receptor is evaluated. Within DOCK 3.5 three methods are available for this evaluation: contact scoring, which measures shape complementarity; force-field scoring, which is an estimate of the enthalpy of the intermolecular interaction; and elec- http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_379.html [4/5/2004 5:39:49 PM]
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