Hydrogen bond donor/acceptor sites

It is unlikely that a given partial-proton-transfer would be overly efficient in aqueous solution. In much the same way as has been argued in the context of the LBHB hypothesis [97], the hydrogen bonding donor/acceptor properties of water and the entropic disorder associated with such a solution are likely to disrupt the hydrogen bond. However, the active sites of many enzymes are sequestered from bulk water, at least to some extent, and may therefore provide... 

Five-membered ring heterocycles are common in numerous pharmaceuticals. In particular, the imidazole core structure, an element of histidine and its decarboxylation metabolite histamine, is often found [53]. The exceptional properties and wide applicability of the imidazole pharmacophore are due to its hydrogen-bond donor/acceptor capabilities and its high affinity for metals (present in many protein active sites, e.g., Zn, Fe, Mg) [54-58]. In addition, peptide-based protease inhibitors with improved pharmacokinetics and bioavailability have been obtained by replacing an amide bond with an imidazole [59]. 

The pharmacophore point types used to derive PharmPrint descriptors are hydrogen-bond acceptor (A), hydrogen-bond donor (D), sites of formal negative (N) and positive (P) charges, and hydrophobic (H) and aromatic (R) groups. A seventh type (X) is used to label all the atoms that are not assigned to any PPP type. 

For binding to occur, a host must possess suitable binding sites with favourable electronic properties such as polarity and hydrogen bond donor/acceptor abilities that complement those of the guest. Cyclophanes such as I, calixarenes II, homocalixarenes IH, and resor-cinarenes FV fulfil these requirements (Scheme 12.1). Cucurbiturils V are water soluble container molecules without aromatic subunits. Therefore, both electrostatic interaction other than cation- r interaction and hydrophobic interaction play a dominant role. 

Structural refinement of these host molecules was later pursued by the same group on a double track. In the non-covalent direction, studies were finalized to the design of calix[5]arene pentols fitted, at the wider rim, with a molecular hook capable of facilitating Cgo and C o capsule formation via additional self-assembling interactions between the two sub-units. To this end, ureido 2a [11] and 2,2 -bipyridyl (bpy) derivative 2b [12] were endowed with a self-complementary hydrogen-bond donor/acceptor group and a metal-acceptor (Ag binding site, respectively. 

Both the selection of classes of appropriate features, and how the bin distribution is accomplished, are the subjects of current research. One recent approach that holds promise is the expansion of 3D feature keys to include pharmacophoric or stereophoric features as surrogates for the macromolecular receptor site. Each of these features is comprised of a collection of three or four atomic environments (selected from a list including hydrogen-bond donors, acceptors, etc.) in association with interatomic distance ranges. Another theme is the introduction of a 3D surface descriptor as the basis for matching. 

If the solvent that is selected is polar (e.g., acetone, acetonitrile, chloroform, dimethylsulfoxide, and methanol), there are stronger dipole interactions between solvent and solute, especially if the solute molecule also contains polar bonds. The interactions between the polar solvent and a polar solute are likely to be stronger than the interactions between the solvent and tetramethylsilane (TMS, which is nonpolar), and the result is that the observed chemical shift of the molecule of interest will be shifted with respect to the observed chemical shift in a nonpolar solvent. The magnitude of this solvent-induced shift can be on the order of several tenths of a parts per million in a proton spectrum. Furthermore, simply changing the concentration of the solute can result in chemical shift changes, especially for environments near a hydrogen bond donor/acceptor or an exchangeable site. 

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