Probe pharmacophoric

The descriptors developed to characterize the substrate chemotypes are obtained from a mixture of molecular orbital calculations and GRID probe-pharmacophore recognition. Molecular orbital calculations to compute the substrate s electron density distribution are the first to be performed. All atom charges are determined using the AMI Hamiltonian. Then the computed charges are used to derive a 3D pharmacophore based on the molecular electrostatic potential (MEP) around the substrate molecules. 

A widely used 3-D QSAR method that makes use of PLS is comparative molecular field analysis (CoMFA), in which a probe atom is used to calculate the steric and electronic fields at numerous points in a 3D lattice within which the molecules have been aligned. Poso et al. [56] used the technique to model the binding of coumarins to cytochrome P450 2A5, with similar results to those obtained by Bravi and Wikel [55]. Shi et al. [57] used it to model the estrogen receptor binding of a large diverse set of compounds, and Cavalli et al. [58] used it to develop a pharmacophore for hERG potassium... 

The form and shape of a molecule (i.e. its steric and geometric features) derive directly from the molecular genotype , but they cannot be observed without a probe. Furthermore, they vary with the conformational, ionization and tautomeric state of the compound. Thus, the computed molecular volume can vary by around 10% as a function of conformation. The same is true of the molecular surface area, whereas the key (i.e. pharmacophoric) intramolecular distances can vary much more. 

Chalcones Chemical library probed with pharmacophore Ligands active in vitro and in vivo [118]... 

Figure 16.5 Resulting pharmacophore for P-gp actively transported molecules. The depicted molecule is the analgesic (narcotic) sufentanil. The colored areas around the molecules are the GRID fields produced by the molecule yellow for DRY probe, green for TIP probe and blue for N1 probe. Reprinted with permission from ref. [53], Copyright 2005 American Chemical Society.

Figure 16.6 A graphical representation of the most important 3D pharmacophoric GRIND features for the cimetidine substrate as a reference compound. The colored areas around the molecule are the GRID MIFs calculated with the O (red) and N1 (blue) probes. Reprinted with permission from ref. [54]. Copyright 2006 American Chemical Society.

Guanidines are basic molecules (pA of guanidine = 12.5) with a capacity to form intermolecular contacts mediated by H-bonding interactions. Consequently, they are potentially useful pharmacophores in medicinal chemistry, 1 have proven applications as artificial sweeteners,2,3 and are useful as probes in academic studies of intermolecular associations, including su-pramolecular complexes. Expedited access to these molecules via solid-phase synthesis is therefore a worthy goal. This chapter outlines various... 

The elucidation of structural pharmacophores in the Kvl.5 channel pore has not been nearly as extensive as analogous efforts conducted on hERG [69]. Briefly, in these types of studies, a drug of interest is used to probe a battery of single amino acid substituted channels with properties similar to wild type channels, to scan a structural domain and identify de-... 

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