H-bond potentials

An attempt to consider the influence of substituents on H-bond potentials was described later in [47]. Here the molecular H-bonding potential (MHBP) is calculated as follows ... 

Using Eq. (14) it is now possible to calculate from Emi values (see the results of such calculation for 15 ideal complexes in Table 6.4). Thus, for each specific pair of atoms participating in an H-bond, the H-bonding potential can be calculated on the basis of Eqs. (3), (11) and (14). Examples of such potentials for O—H O complexes are presented in Fig. 6.4. 

Fig. 6.4 H-bond potentials for OH O complexes. The bold curve corresponds to Goodford s fixed potential for all OH O complexes.

H-bonding potential Molecular weight/size PSA Intestinal metabolism Transport mechanisms Native surfactants Intestinal secretions, e.g. mucous, enzymes Intestinal blood/lymph flow Excipient effects... 

More recently the H-bonding potential (an estimate of hydrophilicity) and surface charge characteristics of a molecule have been used as predictors of passive Pm and intestinal absorption [17, 18], Theoretical models based on the determination of polar surface area (PSA) have been utilised to reasonable... 

Most commonly used is certainly the molecular electrostatic potential. It can be derived from any kind of charge distribution. Usually, the MEP is first calculated on a grid and subsequently transformed to the sphere or Gaussian representation. Quite important is the electron density distribution, which closely models the steric occupancy by a molecule. Other approaches utilize artificial fields for physicochemical properties commonly associated with binding, like a field for the hydrophobicity [193] or H-bonding potential [133,194]. 

None of these methods gives a perfect prediction, particularly because H-bonding potential needs to be overlaid over intrinsic lipophilicity. For this reason Lipinski s rule-of-five becomes valuable in defining the outer limits in which chemists can work [9]. Lipinski defined the boundaries of good absorption potential by demonstrating that poor permeability is produced by ... 

Fig. 3.6 Removal of H-bond donors as a synthetic strategy for a series of azole-containing endothelin antagonists aimed at improving bioavailability by lowering H-bonding potential [10].

The work of Young et al. [1] provides a classic example of the role of increased H-bonding potential in preventing access to the CNS (crossing capillary and astrocyte cell membranes Figure 4.2). In this example Alog P provided a measure of H-bonding potential. 

Vedani, A., Dunitz, J.D. Lone-pair Directionality of H-bond Potential Functions for Molecular Mechanics Calculations the Inhibition of Human Carbonic Anhydrase II by Sulfonamides. 

Nonetheless, the early disagreement of counterpoise corrected H-bond potentials with experiment spawned a number of variants of the technique which reduced the BSSE correction and left the potential more attractive than if the full error were removed. Some of these methods justified themselves on the grounds that the electrons of one molecule should not expand into the orbital space of the partner molecule that is already occupied by elec-trons . Hence, damping factors were introduced or more formal means of permitting the electrons of molecule A to partially occupy only the vacant MOs of molecule B, and vice versa - Another technique proposed employing a perturbing charge field gen-... 

O. Tapia, F. Sussman, and E. Poulam,/. Theor. Biol., 71, 49 (1978). Environmental Effects on H-Bond Potentials A SCRF MO CNDO/2 Study of Some Model Systems. 

Modulators and inhibitors of multidrug efflux transporters, such as Pgp, are used to reduce or inhibit MDR, which leads to a failure of the chemotherapy of, for example, cancers, epilepsy, bacterial, parasitic, and fungal diseases. Binding and transport of first-, second-, and third-generation modulators and inhibitors of Pgp take into account the properties of the drug (H-bonding potential, dimensions, and pK values) as well as the properties of the membrane. 

In the independent proton model the H-bond potential well is disconnected from all other vibrations [51]. Unlike the case of electrons in molecules, where the Bom-Oppenheimer approximation applies, this disconnection cannot be on the grounds of significantly differing energy scales. The energies of H-bond vibrations are very similar to those of the heavy atoms. Rather the separation of the two sets of dynamics is... 

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