Numerous molecular 3D-descriptors and alignment methods have been proposed. Examples include CoMFA, Randic molecular profiles, 3DMoRSE code, invariant MK-0683 moments and radial scanning and integration, radial distribution function descriptors, WHIM, length-to-breadth ratios, USR, ROCS, VolSurf, GETAWAY, and shrinkwrap surfaces, to name just a few prominent representatives. In computer MK-4827 graphics, several methods exist for the more general problem of comparing arbitrary 3D objects, including distribution-based shape histograms, the D2 shape descriptor, and, the scaling index method; the viewbased methods of extended Gaussian images, and the light field descriptor; the surface decomposition-based methods -Licarin-B-chemical-structure.gif)
of Zernike moments, REXT, and spherical harmonics descriptors. Spherical harmonics have been used in cheminformatics as a global feature-based parametrization method of molecular shape. Their attractive properties with regard to rotations make them an intuitive and convenient choice as basis functions when searching in a rotational space. A review article by Venkatraman et al. highlights applications of spherical harmonics to protein structure comparison, ligand binding site similarity, protein-protein docking, and virtual screening. Jakobi et al. use spherical harmonics in their ParaFrag approach to derive 3D pharmacophores of molecular fragments. Recently, Ritchie and co-workers have applied the ParaSurf and ParaFit methodologies in a virtual screening study on the directory of useful decoys data set, which motivates 3D shape-property combinations specifically for flexible ligands. The DUD data set was also used in a comparative analysis of the performance of various shape descriptors alone and in combination with property and pharmacophore features. See the section on related methods for further discussion of spherical harmonics approaches. In this work, we introduce a partially rotation-invariant descriptor of molecular shape based on spherical harmonics decomposition coefficients. The idea is to decompose the molecular surface using spherical harmonics and to use the norm of the decomposition coefficients as a description of molecular shape. In this, we take advantage of the fact that the norm of the coefficients does not change under rotation around the z-axis, which we align to the primary axis of the molecule. We retrospectively evaluate our descriptor, and prospectively apply it to screen for novel inhibitors of the enzymes cyclooxygenase-1 and cyclooxygenase-2. Particular focus is on the practical application of the virtual screening technique as an evaluation of its actual suitability for early-phase drug discovery. The inhibitory data obtained from the whole blood assay might be meaningful for further hit optimization. Compounds that are active in this assay are not snatched away by binding to serum albumin, but cross the cell membrane and overcome possible interactions with cellular substances or enzymes. This could explain why compounds 5 and 9 are active in the enzyme assay, but inactive in the whole blood assay. In contrast, compounds 6,10,2and 8, which were moreactive in the whole blood assay, possibly interact with the arachidonic acid pathway in other ways than direct inhibition of COX-1 or COX-2. Also, these compounds might be metabolized by cellular enzymes to more active derivatives, but this hypothesis needs to be tested by further experiments. Compound 8 is of special interest, as it induces PGE2 production up to 322%. This increase could be due to an activation of enzyme activity, possibly by binding to the “inactive” monomer of the COX-homodimer complex.