Binding-site cavity

Consistent with the experimental data, mutation of the purine base nitrogens, i.e. N, 3N, 7N and 9N, showed that replacement of N, 3N and 9N with CH had little effect on binding affinity whereas a similar replacement of 7N led to a loss of 2.8 kcal/mol. The 0.6 kcal/mol gain in affinity for the 1-deaza and 3-deaza AMP analogues was consistent with the hydrophobic nature of this portion of the binding site cavity and the absence of hydrogen bond donors in the vicinity of either heteroatom. 

In this way, MTD descriptors measuring the - steric misfit between the binding site cavity and the considered molecules are calculated as ... 

The MTD-MC method is a modified version of the MTD method, accounting for the existence of several low-energy conformations of molecules used to derive the hypermolecule by overlap. Each molecule is described by a vector of binary variables Ii( )s equal to one if the 5th vertex of the hypermolecule is occupied by the ith molecule in the A th conformation. If more than one low-energy conformation is allowed for a molecule, the conformations considered will be the one which best fits the binding site cavity, i.e. the one with the lowest MTD value ... 

Tlie main assumption of this approach is that the shape of the molecule is closely related to the shape of the - binding site cavity and, as a consequence, to the biological activity. Therefore, a shape reference compound is chosen which represents the binding site cavity, and the similarity (or commonality) measured between the reference shape and the shape of other compounds is used to determine the biological activity of these compounds. As well as the shape similarity measures, other molecular descriptors such as those in - Hansch analysis can be used to evaluate the biological response. The MSA model is thus defined as ... 

Fig. 34.8. Protocol of a classical clocking and scoring procedure. The binding site cavity is characterized by, for example, hydrophobic filled circles), hydrogen-bond donor (lines) and hydrogen-bond acceptor properties (circle segment). Each compound of a database (or real library) is flexibly docked...

In a first step, INH was extracted from the binding site cavity and a commercial docking program (FlexX [16]) was applied to control whether the original binding pose of the X-ray structure could be re-found. For this calculation not the complete protein but only a volume with a radius of 10 A around the binding site was considered. 

Fig. 34.9. X-Ray crystallographically determined binding site of Protox [15], including the co-crystallized inhibitor INH (for structural formula see Fig. 34.10) and a part of the co-factor FAD. Highlighted is Arg98 at the entrance of the binding site cavity, interacting with INH and almost all...

Figure 6 The template theophylline (T) is allowed to interact with the functional monomer methacrylic acid (M) to form a self-assembly. The monomers will interact with theophylline and will form a self-assembly complex mainly based on hydrogen bonding. This self-assembly and the positions of the functional monomers are then frozen and held in place by copolymerization with cross-linker ethyleneglycol dimethacrylate (L). This leads to a rigid polymer scaffold that retains the spatial conformation and thus the specific binding cavity of the original template. After extraction of the template, a molecularly imprinted polymer (MIP) is obtained and the imprinted cavity is able to specifically rebind the template and other, even similar structures are excluded from the binding site cavity.

Definition of the Binding Site Cavities and Regression Analysis... 

In the second step, one or more primary site pockets are identified as seeds for generating larger site cavities consisting of a primary pocket and one or more neighboring secondary pockets. To identify the primary site pockets, the union volume of the superimposed molecules is now divided, usually manually, into distinct binding site cavities (see Figure 3). All ligand atoms that fall into a particular site cavity experience the same environment that is, a specific set of coefficients (c,y of Eq. [7]) will be attributed to each cavity. 

Figure 3 Binding site cavities of a series of antiviral ribonucleosides obtained by the REMOTDISC method. Each site is labeled note that in this example not all space belongs to a site and sites 1, 2, 4, 5, and 7 are not completely enclosed. Reprinted with permission from Ref. 156. Copyright 1989, American Chemical Society.

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