Substituents additional binding sites

The binding site is located at the tip of the subunit within the jelly roll structure (Figure 5.23). The sialic acid moiety of the hemagglutinin inhibitors binds in the center of a broad pocket on the surface of the barrel (Figure 5.24). In addition to this groove there is a hydrophobic channel that can accomodate large hydrophobic substituents at the C2 position of sialic acid (Figures 5.22 and 5.24). 

In addition to the possible C2,C2 -substituent interactions with a hydrophobic pocket in the regulatory domain site, the much higher affinity of calphostin A (Chart 7.1 4a, R1 = R2 = COPh, IC50 = 0.25 pM) compared to calphostin D (4d, R1 = R2 = H, IC50 = 6.4 pM) also points to interaction of the C7,C7 -portion with the binding site [51]. The C2,C2 - and C7,C7 -analogs would be invaluable in understanding the relative importance of each of these interactions. To determine... 

Errors of this magnitude make the useful prediction of free energies a difficult task, when differences of only one to three kcal/mol are involved. Nevertheless, within the error limits of the computed free energy differences, the trend is that relative to 8-methyl-N5-deazapterin or 8-methyl-pterin, the compounds methyl substituted in the 5, 6 or 7 positions are thermodynamically more stable when bound to DHFR largely by virtue of a hydrophobic effect, i.e. methyl substitution reduces the affinity of the ligand for the solvent more than it reduces affinity for the DHFR active-site. The stability of ligand binding to DHFR appears to be optimal with a 6-methyl substituent additional 5-methyl and/or 7-methyl substitution has little effect... 

Moreover, it could be figured out that an effective means to modulate the stereorecognition capabilities of the cinchonan selector motif may be via the carbamate residue. It offers a way of straightforward introduction of bulky alkyl substituents, which may affect the accessibility of active binding sites and/or lead to additional supportive Van der Waals-type interactions. 

Generation of a virtual combinatorial library by finding substituents of a custom scaffold that can be accommodated in the binding site of a molecular target or meet other 3D structural criteria. Once the virtual library is synthesized in the computer, individual members can be selected using structural or additional criteria and synthesized using automated equipment. 

The adamantyl unit provides several positions for the introduction of additional substituents, which opens the road for the further development of this type of ligand (possible fine-tuning of selectivity, creation of new binding sites at the wide rim, etc.). 

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