Purines, binding modes

The availability of different metal ion binding sites in 9-substituted purine and pyrimidine nucleobases and their model compounds has been recently reviewed by Lippert [7]. The distribution of metal ions between various donor atoms depends on the basicity of the donor atom, steric factors, interligand interactions, and on the nature of the metal. Under appropriate reaction conditions most of the heteroatoms in purine and pyrimidine moieties are capable of binding Pt(II) or Pt(IV) [7]. In addition, platinum binding also to the carbon atoms (e.g. to C5 in 1,3-dimethyluracil) has been established [22]. However, the strong preference of platinum coordination to the N7 and N1 sites in purine bases and to the N3 site in pyrimidine bases cannot completely be explained by the negative molecular electrostatic potential associated with these sites [23], Other factors, such as kinetics of various binding modes and steric factors, appear to play an important role in the complexation reactions of platinum compounds. 

The X-ray structure of the complex between PNP and (87) showed that the hydro-phobic interaction dominated the binding mode, and resulted in the disruption of the hydrogen bonding interactions seen in the guanine complex (i.e., Fig. 10.19). To increase the spacing between the hydrophobe and the purine mimetic, compounds (88) and (89)... 

Rebek s second generation of self-replicating molecules [59] which restrain the preassociative bimolecular pathway is a diaminocarbazole-based diimide, a nearly ideal complement to the purine nucleus of adenine. Conformational complications from the switching bound adenine between Watson-Crick and Hoogsteen binding modes are eliminated. 

Figure 4.2 Binding modes for medicines that use the purine site of protein kinases.

Figure 4.3 Binding modes for medicines that extend from the purine site into the selectivity pocket of protein kinases. Key hydrogen bonds are shown as dotted lines and hydrophobic interactions in the selectivity pocket are shown as arcs.

It is difficult to deconvolute how kinase inhibitor binding mode has implications in the clinic. In general, selectivity tends to increase in the order (i) purine site, (ii) selectivity pocket, and (iii) allosteric site. The ability to overcome resistance mutations in cancer therapy tends to be inversely related to this selectivity pattern. Accordingly, allosteric kinase inhibition may become a preferred mechanism for clinical indications other than cancer. 

Figure 6.9 Co-crystal structure of ATP bound to PI3K-y. The binding mode is characterized by the hinge region interaction of the purine ring nitrogen with the Val-882 backbone amide. Additional interactions shown are H-bonds from Ser-806 and Lys-833 to the phosphate and from the exocyclic amine to Glu-880.

Figure 13.12 Purine fragment binding mode 4FCP, displayed using PyMOL...

For the purines, only in the case of adenine has the [N3 + N9] bridging mode been observed (76-78). This further highlights the difference in binding patterns between the N3 of A and G. A recent example is seen in the Pd2-adenine complex, 18, formed in reactions of 19 with... 

Attention has been drawn to the fact that the size and shape of the purine-pyrimidine base pair in this case is rather similar to the size and shape of the benzo[a]pyrene nucleus, which is a powerful carcinogen ( ,). That carcinogen is known to bind covalently to the N2 position of guanine (15). In the present lattice the planar purine-pyrimidine base pair rests in a position close to the guanine N2. Thus, this mode of interaction may also be a model for the interaction of planar carcinogen molecules with mA. 

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