198 Topics in Current Chemistry Editorial Board: A. de Meijere KN ...

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Supramolecular Synthons and Pattern Recognition 79 additional C(2)-H◊◊◊O(2) and C(8)-H◊◊◊O(2) interactions forced by the geometry of the A.T/U base pair (Scheme 12). Moreover, the repulsive secondary interaction between the O(2) atom of T/U and N(1) or N(7) atom of A is now balanced by a stabilising hydrogen bond. In recognition motifs where the C-H◊◊◊O hydrogen bond is a viable contributor, the hydrogen bonding abilities of thymine and uracil must be considered in a different light. The sp 2 C-H of uracil has a greatly enhanced hydrogen bonding capability compared to the CH 3 hydrogens of thymine because of its higher acidity. It has been shown that the geometries and energies of DNA base triplets (CG):C, (TA):T, (AT):A and (GC):G and their matching in the homologous recombination can be explained by the auxiliary C-H◊◊◊O and C-H◊◊◊N hydrogen bonds [58]. It is clear that C-H◊◊◊O and C-H◊◊◊N hydrogen bonds are abundant in biological macromolecules and despite their small enthalpic contribution (0.5–2.0 kcal mol –1 ) [59], they seem to exert pronounced structural and functional effects [60]. 7.2 Pattern Recognition in Drug-Enzyme Binding The idea of recognition between enzyme and substrate goes back more than one hundred years to Fischer’s “lock-and-key” analogy of enzyme catalysis [61]. Drug-receptor recognition and binding is, however, not as simple as the lockand-key analogy and may be more likened to a hand fitting into a glove. Both the drug (or ligand) as well as the receptor (or active site) are flexible and yet have very specific requirements for mutual recognition [62]. It is important to note that the docking of a drug molecule into the active site of a receptor protein is governed by the same combination of forces that control crystallisation, namely electrostatic forces, hydrogen bonding interactions, van der Waals forces and hydrophobic effects, the last factor being responsible for the exclusion of water a b c d Scheme 12 a – d. C-H◊◊◊O hydrogen bonds in: a Watson-Crick U . A pair; b Hoogsteen T . A pair; c O8G◊ A pair (O8G: 7,8-dihydro-8-oxoguanine); d Hoogsteen C + ◊ G pair. For patterns a, b and c, see [57]; pattern d is putative
80 A. Nangia · G.R. Desiraju from nonpolar regions of the macromolecule. It is well known that the difference between a molecule that binds to the active site with minimal side effects, and hence a potential drug candidate, and the numerous ligands that do not is usually a very small structural difference in atom type, position or stereochemistry. The objective of rational drug design is therefore to predict new molecules or analogues of known drugs which will have favourable interactions with a protein of known structure [63, 64]. The three crucial inputs for structure-based ligand design are: (1) the molecular structure of the ligand; (2) the shape of the macromolecular receptor protein; and (3) the typical intermolecular interaction patterns between ligand and receptor. The last of these is within the scope of this article and is discussed here. The number of accurate crystallographically resolved ligand-protein structures is still not large and hence a systematic, statistical analysis of their interaction geometry is not possible. However, the enormous wealth of information on small molecule crystallography in the CSD can be retrieved to extract orientational preferences for interaction around different functional groups. Klebe has presented composite crystal field environments for the approach of different donor hydrogens to various acceptor atoms,in effect compiling a hydrogen bond geometry data file relevant to drug-protein binding [65]. The histograms and scattergrams for four selected functional groups from the CSD and Protein Data Bank (PDB) are given in Figs. 3 and 4. A comparison of these figures suggests that patterns and motifs observed in the low molecular weight ligand structures are a faithful representation of the spatial orientation of interaction geometry between ligands and proteins. The application of the CSD also extends to ligand conformation. It has been shown that ligand conformations in small-molecule a b c d Fig. 3. Scatterplots and histograms of the spatial distribution of donor sites about different acceptor functional groups. Non-bonded contacts are as retrieved from the CSD (Adapted from Klebe [65]). The definition of the spherical polar coordinates F and Q are given in this paper
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198 Topics in Current Chemistry Edi
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Design of Organic Solids Volume Edi
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Volume Editors Prof. Dr. Edwin Webe
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VIII preface tion at an amazing lev
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Contents of Volume 196 Carbon Rich
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2 J.P. Glusker 5 Interactions of Pl
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4 J.P. Glusker Perturbations to the
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6 J.P. Glusker 2.1 Sources of Cryst
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8 J.P. Glusker other induced, will
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10 J.P. Glusker The forces here hav
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12 J.P. Glusker lographic structure
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14 J.P. Glusker a c Fig. 6 a - c. D
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16 J.P. Glusker hydrogen bond H◊
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18 J.P. Glusker Fig. 9. Citric acid
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20 J.P. Glusker peptide plane and a
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22 J.P. Glusker 4.5 F◊◊◊H Int
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24 J.P. Glusker rine-containing com
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26 J.P. Glusker Fig. 17. The packin
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132 Y. Aoyama 4 Catalysis . . . . .
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134 Y. Aoyama 2.2 Symmetry-Controll
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136 Y. Aoyama A trigonal centre is
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138 Y. Aoyama 18 19 Fig. 5. 2D net
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140 Y. Aoyama 24 ded (O-H◊◊◊O
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142 Y. Aoyama 2.4 Interaction-Suppo
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144 Y. Aoyama In the presence of a
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146 Y. Aoyama clusion compounds (se
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148 Y. Aoyama are intriguing guests
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150 Y. Aoyama The tuning or enginee
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152 Y. Aoyama Fig. 16. Binding isot
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154 Y. Aoyama The desorption of the
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156 Y. Aoyama Fig. 17. Suggested me
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158 Y. Aoyama 5 Concluding Remarks
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160 Y. Aoyama 4. Hölderich W, Hess
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Crystalline Polymorphism of Organic
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Author Index Volumes 151-198 Author
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Author Index Volumes 151 - 198 2 1
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Author Index Volumes 151 - 198 2 ]
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Springer and the environment At Spr
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