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

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Supramolecular Synthons and Pattern Recognition 81 a b c d Fig. 4. Scatterplots and histograms of the spatial distribution of acceptor or donor sites in ligand molecules about different functional groups of active site residues in ligand-protein crystal structures (PDB) (Adapted from [65]). Note that the distributions are more smeared when compared with those in Fig. 3 crystal structures offer a good representation of their conformations in ligandenzyme complexes [64]. While adopting this approach, it is reassuring to note that the average densities found for crystal structures of small organic compounds and for the inner regions of macromolecular proteins are in the same range. In summary, therefore, CSD derived geometries offer a considerable simplification in the analysis and understanding of drug-receptor interaction patterns (see also the article by J.P. Glusker in this volume). 7.3 Pharmacophore Model The repetitive nature of enzyme-ligand patterns leads to the concept of the pharmacophore model which postulates that there is a minimum and essential set of functional groups that a molecule must possess in a specific geometrical arrangement to be recognised by the receptor [66]. The pharmacophore model can be generated by identifying the chemically important functional groups that are common to the molecules that bind to a given receptor. We have accordingly examined the b-lactam class of antibiotics [67]. Geometrical details from a total of 114 b-lactams containing the fragment 56 were retrieved from the CSD (Version 5.05) and categorised into biologically active (80) and inactive (30) compounds. The superposition plot of 12 randomly selec- 56
82 A. Nangia · G.R. Desiraju ted active compounds containing the b-lactam-C-CO 2 fragment shows that the lactam carbonyl and the carboxylate groups are bunched in their specific, narrow regions and do not show much variation in the positioning of the fourmembered b-lactam ring and and the connecting carbon linkage (Fig. 5a). This depiction of functional groups is therefore a good pharmacophore model for the binding of the b-lactam with the receptor protein. The corresponding superposition plot for the 12 randomly selected inactive b-lactams shows considerable variation in the positioning of the lactam ring and the connecting -C- linkage (Fig. 5b). Thus, the 3D structures of a class of drug molecules, together with their biological activity, can be profitably utilised to develop a pharmacophore model for the drug. Furthermore, the observation that the active molecules are tightly bunched and adopt a nearly similar conformation in the pharmocophore a b Fig. 5 a, b. Superposition plot of 12 randomly chosen b-lactams containing fragment 56 from: a the active diagonal; b the inactive diagonal of the Woodward (h) – Cohen (c) scatterplot (Taken from Nangia et al. [67])
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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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28 J.P. Glusker bind to a metal ion
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Page 139 and 140: 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 - 198 213
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Author Index Volumes 151 - 198 2 ]
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Springer and the environment At Spr
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198 Topics in Current Chemistry Editorial Board: A. de Meijere KN ...

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