Noncovalent compounds

While covalent compounds, which are synthesized by regioselective connection of functional groups in any combination of educts, noncovalent compounds usually depend on the fitting of molecules. Five binding effects or forces or a combination of them coimect such molecules. 

Mass spectrometric studies of noncovalent compounds, particularly, catenanes 06OBC2825. 

AmpC P-Lactamase. A map of hot spots was constructed from the X-ray structure of AmpC P-lactamase and a university version of the program DOCK was used to search for noncovalent inhibitors in 229,810 compounds of the ACD database. Of 56 tested compounds three had values <650pM, for example, compound 41 Ki = 26pM Fig. 16.6) [117]. The experimental X-ray structure of its complex with AmpC P-lactamase closely resembles the predicted binding mode. 

Dendrimers are complex but well-defined chemical compounds, with a treelike structure, a high degree of order, and the possibility of containing selected chemical units in predetermined sites of their structure [4]. Dendrimer chemistry is a rapidly expanding field for both basic and applicative reasons [5]. From a topological viewpoint, dendrimers contain three different regions core, branches, and surface. Luminescent units can be incorporated in different regions of a dendritic structure and can also be noncovalently hosted in the cavities of a dendrimer or associated at the dendrimer surface as schematically shown in Fig. 1 [6]. 

Many compounds that damage DNA via radical intermediates have been identified. Some of the agents, such as bleomycin and the enediynes, damage DNA primarily through abstraction of hydrogen atoms. ° In these cases, chemical reactions are directed to certain positions on the DNA backbone by noncovalent binding that places the reactive intermediates in close proximity to particular deoxyribose sugar residues. Similar to the reactions of HO described above, small radicals, such as... 

Suitable for fragile compounds (noncovalent complexes and thermally labile species)... 

In contrast to the reactions of the cycloamyloses with esters of carboxylic acids and organophosphorus compounds, the rate of an organic reaction may, in some cases, be modified simply by inclusion of the reactant within the cycloamylose cavity. Noncovalent catalysis may be attributed to either (1) a microsolvent effect derived from the relatively apolar properties of the microscopic cycloamylose cavity or (2) a conformational effect derived from the geometrical requirements of the inclusion process. Kinetically, noncovalent catalysis may be characterized in the same way as covalent catalysis that is, /c2 once again represents the rate of all productive processes that occur within the inclusion complex, and Kd represents the equilibrium constant for dissociation of the complex. 

The nature of the target to be attacked by any drug obviously depends on the specific application. Many cytotoxic metal complexes target DNA because of its importance in replication and cell viability. Coordination compounds offer many binding modes to polynucleotides, including outer-sphere noncovalent binding, metal coordination to nucleobase and phosphate backbone... 

Rotaxanes are the compounds consisting of noncovalent entities called rotor and axle [77], Figure 21 illustrates them schematically. Initially, attempts were made to prepare them by statistical methods, so that the yields were necessarily very low [78-80], Recently, methods have been proposed for their more efficient synthesis, with renewed interest in their unique structure and properties. Section 4.1 summarizes some of the typical results obtained. 

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. 

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