Conformational flexibility
is a major determinant of the properties of macrocycles and other
drugs in beyond rule of 5 (bRo5) space. Prediction of conformations
is essential for design of drugs in this space, and we have evaluated
three tools for conformational sampling of a set of 10 bRo5 drugs
and clinical candidates in polar and apolar environments. The distance-geometry
based OMEGA was found to yield ensembles spanning larger structure
and property spaces than the ensembles obtained by MOE-LowModeMD (MOE)
and MacroModel (MC). Both MC and OMEGA but not MOE generated different
ensembles for polar and apolar environments. All three conformational
search methods generated conformers similar to the crystal structure
conformers for 9 of the 10 compounds, with OMEGA performing somewhat
better than MOE and MC. MOE and OMEGA found all six conformers of
roxithromycin that were identified by NMR in aqueous solutions, whereas
only OMEGA sampled the three conformers observed in chloroform. We
suggest that characterization of conformers using molecular descriptors,
e.g., the radius of gyration and polar surface area, is preferred
to energy- or root-mean-square deviation-based methods for selection
of biologically relevant conformers in drug discovery in bRo5 space.
Novel P2X 7 Receptor Antagonists. -The synthesis and pharmacological evaluation of a series of novel cyclic imides that are potent P2X 7 receptor antagonists is disclosed. -(ALCARAZ*, L.; et al.; Bioorg. Med. Chem. Lett. 13 (2003) 22, 4043-4046; Dep. Med. Chem., Astra Charnwood, Loughborough, Leicestershire LE11 5RH, UK; Eng.) -H. Haber
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