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Document Figure 10 Binding mode of 2-guanidinobenzimidazole to T.brucei GAPDH as predicted by DOCK. The benzimidazole moiety occupies roughly the position occupied by adenine in the holo-enzyme, whereas the guanidino group a salt bridge to Asp37. the basis of structural rigidity, chemical stability, solubility, and electrostatic complementarity. The latter property was evaluated with the program DELPHI [85]. Page 383 Each of the sixteen compounds was tested for GAPDH inhibition (Table 7). Half of them were inactive while the other ones showed inhibition in a range between 1.2 and 25 mM. Unfortunately, there appears to be no correlation between the DOCK scores and the IC 50 values. For examples, norepinephrine and 1,3-diphenylguanidine are inactive while they have a better score than 2- guanidinobenzimidazole (Figure 10), the compound with the best IC 50. Also, it appeared that the two different receptor descriptions used led to almost completely different lists of compounds. Only 156 molecules occurred in both lists of top-scoring molecules. In the modeled binding mode all of the inhibitors occupy roughly the same position as the purine ring of NAD in the crystal structure of GAPDH. While the values obtained for IC 50 are indicative of poor inhibition, one has to keep in mind that adenosine exhibits an IC 50 of 50 mM [13]. By using the program DOCK we were able to discover ligands that have a substantially higher affinity for GAPDH than the natural ligand. C. Phosphoglycerate Kinase: Leads from the Past The starting point for drug design in the case of PGK is quite different from TIM or GAPDH because a number of nonsubstrate-like inhibitors have been http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_383.html (1 of 2) [4/5/2004 5:41:28 PM]
Document Figure 11 Two-dimensional structure of SPADNS, a micromolar inhibitor of T.brucei PGK. Page 384 discussed in the literature. Suramin inhibits glycosomal PGK of T. brucei with a K i of 8.0 μM [69]. In addition a number of yeast PGK inhibitors are known: gallic acid with a K i = 0.4 mM [86], hydroxyethylidene biphosphate with a K i = 24 mM [87]. 1,3,6-naphthalenetrisulphonic acid with a K i = 5.5 mM, and 2-(p- sulphophenylazo)-1,8-dihydroxy-3,6-disulphonic acid, also known as SPADNS (Figure 11), with a K i = 126 μM [87]. None of the four yeast PGK inhibitors are potent, but, for SPADNS, the binding mode has been further characterized. Studies by Williams et al. [87] have demonstrated that SPADNS is directly competitive with both enzyme substrates, 3-phosphoglycerate and ATP. Moreover, by 600 MHz 1H-NMR it was shown that SPADNS interacts with the nucleotide binding site while the conformation of the enzyme changes substantially [87]. Since the four yeast PGK inhibitors are commercially available it was logical to test them for T. brucei PGK inhibition. The first three compounds were active in the millimolar range. However, SPADNS exhibited a K i of 10.0 μM in these in preliminary tests [88]. Moreover, when assayed against a commercially available rabbit muscle PGK, SPADNS had no influence on the enzyme kinetics up to a concentration of 250 μM [88]. In conclusion, SPADNS appears to be an excellent lead because of its potency and selectivity. Crystallographic experiments to determine its binding mode to T. brucei PGK are underway. IV. Lead Optimization: Glycosomal Gapdh From the selectivity point of view the adenosine binding site of GAPDH is attractive for drug design, as we explained in Section II.B. Unfortunately, inhibition studies on T. brucei and L. mexicana GAPDH revealed the poor affinity of our natural lead adenosine with IC 50 values of 100 mM and 50 mM, respectively. Moreover, adenosine is an “antiselective” lead because the IC 50 http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_384.html [4/5/2004 5:41:34 PM]
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Structure-based Drug Design 14 Stru
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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