Diameter Is a Key 3D Characteristic for Assessments of Efficient Inhibitors of Protein-Protein Interactions.

Three-dimensional (3D) molecular descriptors, including physicochemical and shape properties, for protein-protein interaction (PPI) interface inhibitors have become a topic of discussion. However, the relationships between such properties and binding free energy have not been adequately investigated. In this study, we focused on identifying key 3D molecular descriptors related to the binding free energy and/or the ligand efficiency (LE) of PPI interface inhibitors. A positive correlation was found between the binding free energy and the diameter (D) of cylindrical 3D molecules, in addition to a correlation between LE and D/heavy atom count (HAC). In addition, we showed a correlation between LE and D/HAC for macrocyclic compounds, suggesting that the present findings could be applied during assessments of the potential of macrocyclic PPI interface inhibitors in drug discovery processes.

Sesamin extends lifespan through pathways related to dietary restriction in Caenorhabditis elegans.

PURPOSE: Sesamin, a polyphenolic compound found in sesame seeds, has been reported to exert a variety of beneficial health effects. We have previously reported that sesamin increases the lifespan of Caenorhabditis elegans. In this study, we investigated the molecular mechanisms underlying the longevity effect of sesamin in C. elegans. METHODS: Starting from three days of age, Caenorhabditis elegans animals were fed a standard diet alone or supplemented with sesamin. A C. elegans genome array was used to perform a comprehensive expression analysis. Genes that showed differential expression were validated using real-time PCR. Mutant or RNAi-treated animals were fed sesamin, and the lifespan was determined to identify the genes involved in the longevity effects of sesamin. RESULTS: The microarray analysis revealed that endoplasmic reticulum unfolded protein response-related genes, which have been reported to show decreased expression under conditions of SIR-2.1/Sirtuin 1 (SIRT1) overexpression, were downregulated in animals supplemented with sesamin. Sesamin failed to extend the lifespan of sir-2.1 knockdown animals and of sir-2.1 loss-of-function mutants. Sesamin was also ineffective in bec-1 RNAi-treated animals; bec-1 is a key regulator of autophagy, and is necessary for longevity induced by sir-2.1 overexpression. Furthermore, the heterozygotic mutation of daf-15, which encodes the target of rapamycin (TOR)-binding partner Raptor, abolished lifespan extension by sesamin. Moreover, sesamin did not prolong the lifespan of loss-of-function mutants of aak-2, which encodes the AMP-activated protein kinase (AMPK). CONCLUSIONS: Sesamin extends the lifespan of C. elegans through several dietary restriction-related signaling pathways, including processes requiring SIRT1, TOR, and AMPK.

An Intriguing Correlation Based on the Superimposition of Residue Pairs with Inhibitors that Target Protein-Protein Interfaces.

Druggable sites on protein-protein interfaces are difficult to predict. To survey inhibitor-binding sites onto which residues are superimposed at protein-protein interfaces, we analyzed publicly available information for 39 inhibitors that target the protein-protein interfaces of 8 drug targets. By focusing on the differences between residues that were superimposed with inhibitors and non-superimposed residues, we observed clear differences in the distances and changes in the solvent-accessible surface areas (∆SASA). Based on the observation that two or more residues were superimposed onto inhibitors in 37 (95%) of 39 protein-inhibitor complexes, we focused on the two-residue relationships. Application of a cross-validation procedure confirmed a linear negative correlation between the absolute value of the dihedral angle and the sum of the ∆SASAs of the residues. Finally, we applied the regression equation of this correlation to four inhibitors that bind to new sites not bound by the 39 inhibitors as well as additional inhibitors of different targets. Our results shed light on the two-residue correlation between the absolute value of the dihedral angle and the sum of the ∆SASA, which may be a useful relationship for identifying the key two-residues as potential targets of protein-protein interfaces.

Molecular recognition of alpha,beta-unsaturated carbonyl compounds using aluminum tris(2,6-diphenylphenoxide) (ATPH): structural and conformational analysis of ATPH complexes and application to the selective vinylogous aldol reaction.

Various alpha,beta-unsaturated carbonyl compounds were coordinated with aluminum tris(2,6-diphenylphenoxide) (ATPH) to give the corresponding Lewis acid-base complexes in a distinctive coordination fashion (selective coordination). ATPH recognizes carbonyl substrates and subsequently orients itself as it forms a stable complex through selective coordination with the carbonyl oxygen. Selective coordination also confers a conformational preference to each carbonyl compound under the steric and electronic influence of ATPH, which enables the vinylogous aldol reaction of alpha,beta-unsaturated carbonyl compounds to give the corresponding gamma-aldol products with different regio- and stereoselectivities.

Synthesis of (-)-TAN-2483A. Revision of the structures and syntheses of (+/-)-FD-211 (waol A) and (+/-)-FD-212 (waol B).

[structure: see text] The structure of waol A has been revised from 1 to 6, the vinylogue of TAN-2483 A (5). Aldol reaction of 10b(c) with 2,4-hexadienal (11) affords 9b(c), which is subjected to iodoetherification with bis(sym-collidine)IPF(6) to provide 8b(c). Treatment with Et(3)N in CH(2)Cl(2) completes three-step syntheses of TAN-2483A (5) and waol A (6).