Here, the comparisons of performance of nine consensus scoring strategies, in which multiple scoring functions were used simultaneously to evaluate candidate structures for a protein-ligand complex, in combination with nine scoring functions (FlexX score, GOLD score, PMF score, DOCK score, ChemScore, DrugScore, PLP, ScreenScore, and X-Score), were carried out. The systematic naming of consensus scoring strategies was also proposed. Our results demonstrate that choosing the most appropriate type of consensus score is essential for model selection in computational docking; although the vote-by-number strategy was an effective selection method, the number-by-number and rank-by-number strategies were more appropriate when computational tractability was taken into account. By incorporating these consensus scores into the FlexX program, reasonable complex models can be obtained more efficiently than those selected by independent FlexX scores. These strategies might also improve the scoring of other docking programs, and more-effective structure-based drug design should result from these improvements.

No abstract

In the present study we identified the epitopes of antibodies against amyloid beta-(1-42)-peptide (Abeta1-42): 4G8 reacted with peptides corresponding to residues 17-21, 6F/3D reacted with peptides corresponding to residues 9-14, and anti 5-10 reacted with peptides corresponding to residues 5-10. The study also yielded some insight into the Abeta1-42 structures resulting from differences in pH. An ELISA study using monoclonal antibodies showed that pH-dependent conformational changes occur in the 6F/3D and 4G8 epitopes modified at pH 4.6, but not in the sequences recognized by anti 1-7 and anti 5-10. This was unique to Abeta1-40 and Abeta1-42 and did not occur with Abeta1-16 or Abeta17-42. The reactivity profile of 4G8 was not affected by blockage of histidine residues of pH-modified Abeta1-40 and Abeta1-42 with diethyl pyrocarbonate; however, the mutant [Gln(11)]Abeta1-40 abrogated the unique pH-dependence towards 4G8 observed with Abeta1-40. These findings suggest that these epitopes are cryptic at pH 4.6, and that Glu(11) is responsible for the changes. We suggest that the abnormal folding of 6F/3D epitope affected by pH masked the 4G8 epitope. A study of the binding of metal ions to Abeta1-42 suggested that Cu(2+) and Zn(2+) induced a conformational transition around the 6F/3D region at pH 7.4, but did not affect the region when it was modified at pH 4.6. However, Fe(2+) had no effect, irrespective of pH. Abeta modified at pH 4.6 appeared to be relatively resistant to proteinase K compared with Abetas modified at pH 7.4, and the former might be preferentially internalized and accumulated in a human glial cell. Our findings suggest the importance of microenvironmental changes, such as pH, in the early stage of formation of Abeta aggregates in the glial cell.

No abstract

We designed and synthesized small-molecule activator protein-1 (AP-1) inhibitors based on a three-dimensional (3D) pharmacophore model that we had previously derived from a cyclic decapeptide exhibiting AP-1 inhibitory activity. New AP-1 inhibitors with a 1-thia-4-azaspiro[4.5]decane or a benzophenone scaffold, which inhibit the DNA-binding and transactivation activities of AP-1, were discovered using a "lead hopping" procedure. An additional investigation of the benzophenone analogues confirmed the reliability of the pharmacophore model, its utility to discover AP-1 inhibitors, and the potency of the benzophenone derivatives as a lead series.