Enzyme-ligand interactions

The final part is devoted to a survey of molecular properties of special interest to the medicinal chemist. The Theory of Atoms in Molecules by R. F.W. Bader et al., presented in Chapter 7, enables the quantitative use of chemical concepts, for example those of the functional group in organic chemistry or molecular similarity in medicinal chemistry, for prediction and understanding of chemical processes. This contribution also discusses possible applications of the theory to QSAR. Another important property that can be derived by use of QC calculations is the molecular electrostatic potential. J.S. Murray and P. Politzer describe the use of this property for description of noncovalent interactions between ligand and receptor, and the design of new compounds with specific features (Chapter 8). In Chapter 9, H.D. and M. Holtje describe the use of QC methods to parameterize force-field parameters, and applications to a pharmacophore search of enzyme inhibitors. The authors also show the use of QC methods for investigation of charge-transfer complexes. 

Hansch, C. and Klein, T.E. (1986) Molecular graphics and QSAR in the study of enzyme-ligand interactions. On the definition of bioreceptors. Accounts of Chemical Research, 19, 392-400. 

Kjellander, B., Masimirembwa, C.M. and Zamora, I. (2007) Exploration of enzyme-ligand interactions in CYP2D6 3A4 homology models and crystal structures using a novel computational approach. Journal of Chemical Information and Modeling, 47 (3), 1234-1247. 

The information contained in karma s knowledge bases is based upon quantitative structure-activity relationships (QSAR), kinetic data, and structural chemistry. The combination of QSAR and kinetic data allows for the study of enzyme-ligand interactions. The Hansch approach to QSAR, based on a set of congeners, states ... 

KARMA describes the interactions for enzyme-ligand binding using QSAR equations and parameters, and the structural information of the congener data. These interactions, with illustrative examples, are shown below ... 

Circular dichroism Secondary structure of proteins, interaction between ligands and proteins, binding of metals at active sites in enzymes 1 )... 

B Canyuk, SP Craig III, AE Eakin. Bacterial complementation as a means to test enzyme-ligand interactions. Appl Microbiol Biotechnol 50 181-186, 1998. 

Figure 7.8. The substrate interaction at the active site of an enzyme. The interaction of tetra-A/,A/,A/,A/-acetylchitotetraose (NAG4) with amino acid residues at the active site of lysozyme (ILZC.pdb) can be viewed/saved at PDBsum server (Enyme Structure Database->PDBsum->LIGPLOT of interactions under Ligand) linked to the Enzyme Structure Database.

Extrinsic Cotton effects are due to the inherent dissymmetry of the enzyme-bound chromophore (an inherent effect) and/or to the interactions of the chromophore with the encompassing dissymmetric environment (interactive effects). The inherent effects are those which the free chromophore would exhibit if its conformation were identical with that of the enzyme-bound form. The interactive effects result from protein-ligand interactions or ligand-ligand interactions. The main problem in interpretation of die CD of enzyme-bound chromophores is distinguishing between the inherent and the interactive effects. 

G Naray-Szabo (1984) Quantum chemical calculation of the enzyme ligand interaction energy for trypsin inhibition by benzamidines, J Am Chem Soc 106( 16 ) 4584—4589... 

Table 4 Geometrical descriptors E/L (enzyme/ligand) interaction and ligand internal energies [85]...

Isomer Isozyme N-C-C-N dihedral angle n Ar/Ar distance (A) Enzyme/ligand interaction energy (kcal/mol) Ligand internal energy (kcal/mol)... 

Site-specifically modified RNAs have been used in many applications to examine RNA stmcture-function relationships, RNA-protein interactions, RNA-ligand interactions, and RNA-catalysis mechanisms. Some earlier studies demonstrated the use of synthetic oligonucleotides to probe the roles of specific functional groups and detailed mechanisms in ribozyme catalysis (55). The synthesis of nucleoside analogs allows for a full-range of chemical diversity (e.g., inductive effects, space-filling capacity, etc.) to be explored, such that quantitative stmcture activity relationships can be determined for RNA enzymes and other biologically important RNAs (56). 

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