Synthesis and biological properties of aryl methyl sulfones.

A novel group of aryl methyl sulfones based on nonsteroidal anti-inflammatory compounds exhibiting a methyl sulfone instead of the acetic or propionic acid group was designed, synthesized and evaluated in vitro for inhibition against the human cyclooxygenase of COX-1 and COX-2 isoenzymes and in vivo for anti-inflammatory activity using the carrageenan induced rat paw edema model in rats. Also, in vitro chemosensitivity and in vivo analgesic and intestinal side effects were determined for defining the therapeutic and safety profile. Molecular modeling assisted the design of compounds and the interpretation of the experimental results.

Dimerization Mechanism of Alzheimer Aβ Peptides: The High Content of Intrapeptide-Stabilized Conformations in A2V and A2T Heterozygous Dimers Retards Amyloid Fibril Formation.

Amyloid beta (Aβ) oligomerization is associated with the origin and progression of Alzheimer's disease (AD). While the A2V mutation enhances aggregation kinetics and toxicity, mixtures of wild-type (WT) and A2V, and also WT and A2T, peptides retard fibril formation and protect against AD. In this study, we simulate the equilibrium ensemble of WT:A2T Aβ dimer by means of extensive atomistic replica exchange molecular dynamics and compare our results with previous equivalent simulations of A2V:A2V, WT:WT, and WT:A2V Aβ dimers for a total time scale of nearly 0.

Energetic contributions of residues to the formation of early amyloid-β oligomers.

Low-weight amyloid-β (Aβ) oligomers formed at early stages of oligomerization rather than fibril assemblies seem to be the toxic components that drive neurodegeneration in Alzheimer's disease. Unfortunately, detailed knowledge of the structure of these early oligomers at the residue level is not yet available. In this study, we performed all-atom explicit solvent molecular dynamics simulations to examine the oligomerization process of Aβ10-35 monomers when forming dimers, trimers, tetramers and octamers, with four independent simulations of a total simulated time of 3 μs for each oligomer system.

Assessing the suitability of the multilevel strategy for the conformational analysis of small ligands.

Predicting the conformational preferences of flexible compounds is a challenging problem in drug design, where the recognition between ligand and receptor is affected by the ability of the interacting partners to adopt a favorable conformation for the binding. To explore the conformational space of flexible ligands and to obtain the relative free energy of the conformation wells, we have recently reported a multilevel computational strategy that relies on the predominant-state approximation-where the conformational space is partitioned into distinct conformational wells-and combines a low-level method for sampling the conformational minima and high-level ab initio calculations for estimating their relative stability. In this study, we assess the performance of the multilevel strategy for predicting the conformational preferences of a series of structurally related phenylethylamines and streptomycin in aqueous solution.

Evolution of a multicomponent system: computational and mechanistic studies on the chemo- and stereoselectivity of a divergent process.

The evolution of a ternary molecular system (imine, diene and nitrile) is analyzed to disclose the pathways leading to a divergent synthetic outcome. The Lewis acid catalyzed reaction between cyclohexadiene, 2-phenyl-indol-3-one and acetonitrile yields the imino-Diels-Alder adduct as the major product together with minor amounts of the Mannich-Ritter-amidine product. The experimental and computational data show that the relative orientation of the initial reactants dictates the synthetic outcome.