Rapid computational mining of large 3D molecular databases is central to generating new drug leads. Accurate virtual screening of large 3D molecular databases requires consideration of the conformational flexibility of the ligand molecules. Ligand flexibility can be included without prohibitively increasing the search time by docking ensembles of precomputed conformers from a conformationally expanded database. A pharmacophore-based docking method whereby conformers of the same or different molecules are overlaid by their largest 3D pharmacophore and simultaneously docked by partial matches to that pharmacophore is presented. The method is implemented in DOCK 4.0.

A search for noncarbohydrate sLe(x) mimics led to the development of quinic acid derivatives as selectin inhibitors. At Wyeth we solved the first cocrystal structure of a small molecule, quinic acid, with E-selectin. In the cocomplex two hydroxyls of quinic acid mimic the calcium-bound fucose of the tetrasaccharide sLe(x). The X-ray structure, together with structure based computational methods, was used to design quinic acid based libraries that were synthesized and evaluated for their ability to block the interaction of sLex with P-selectin. A large number of analogues were prepared using solution-phase parallel synthesis. Selected compounds showed decrease in leukocyte rolling in the IVM mouse model. Compound 2 inhibited neutrophil influx in the murine TIP model and demonstrated good plasma exposure.

The selectins are a family of cell-adhesion proteins that mediate the rolling of leukocytes on activated endothelial cells through the recognition of the carbohydrate epitope sialyl Lewis(x) (sLe(x)). Control of the leukocyte-endothelial cell adhesion process may prove useful in cases where excess recruitment of leukocytes can contribute to acute diseases such as stroke and reperfusion injury and chronic diseases such as psoriasis and rheumatoid arthritis. The development of molecules that block the interactions between sLe(x) and the selectins has become an active area of research. In this review, we will highlight the various approaches taken toward the development of sLe(x) mimetics as antagonists of E- and P-selectin, including the use of structural information about the selectins and their interactions with sLe(x) that have been revealed through the use of NMR, protein crystallography and molecular modeling.

The transition structures for the ene reactions of cyclopropene with ethylene, propene, and cyclopropene have been located with ab initio molecular orbital calculations and the 6-31G* basis set and by DFT calculations with the Becke3LYP functional and the 6-31G* basis set. Several of the transition structures have also been located with CASSCF calculations. Energies of all stationary points were also evaluated with second-order Møller-Plesset theory using the RHF/6-31G* optimized geometry. The geometries of each transition structure and the energetics of each reaction are discussed and compared to the ene reaction of propene with ethylene. Calculations show that the cyclopropene ene reactions have much lower activation barriers than the propene-ethylene ene reaction, in agreement with experimental results. The transition structures have varying degrees of asynchronicity. The stabilities of the possible radical intermediates for each reaction are reflected in the geometries of the transition structures. The relief of strain in a cyclopropene, when acting as the enophile, accounts for the energetic differences in these reactions. The endo transition structure for the dimerization is lower in energy than the exo transition structure by 2.7 kcal/mol at the Becke3LYP/6-31G* + ZPE level of theory. Secondary orbital overlap of a CH bond of the enophile with the π-system at the central carbon of the ene is proposed to account for the preference for the endo transition structure. Barely stable diradical intermediates have been found for both endo and exo cyclopropene dimerization reactions, but it is likely that they are artifacts of the current level of theory.