Discovery and Structure-Activity Relationship (SAR) of a Series of Ethanolamine-Based Direct-Acting Agonists of Sphingosine-1-phosphate (S1P1).

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates a multitude of physiological processes such as lymphocyte trafficking, cardiac function, vascular development, and inflammation. Because of the ability of S1P1 receptor agonists to suppress lymphocyte egress, they have great potential as therapeutic agents in a variety of autoimmune diseases. In this article, the discovery of selective, direct acting S1P1 agonists utilizing an ethanolamine scaffold containing a terminal carboxylic acid is described. Potent S1P1 agonists such as compounds 18a and 19a which have greater than 1000-fold selectivity over S1P3 are described. These compounds efficiently reduce blood lymphocyte counts in rats through 24 h after single doses of 1 and 0.3 mpk, respectively. Pharmacodynamic properties of both compounds are discussed. Compound 19a was further studied in two preclinical models of disease, exhibiting good efficacy in both the rat adjuvant arthritis model (AA) and the mouse experimental autoimmune encephalomyelitis model (EAE).

Optical signatures of molecular dissymmetry: combining theory with experiments to address stereochemical puzzles.

Modern chemistry emerged from the quest to describe the three-dimensional structure of molecules: van't Hoff's tetravalent carbon placed symmetry and dissymmetry at the heart of chemistry. In this Account, we explore how modern theory, synthesis, and spectroscopy can be used in concert to elucidate the symmetry and dissymmetry of molecules and their assemblies. Chiroptical spectroscopy, including optical rotatory dispersion (ORD), electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and Raman optical activity (ROA), measures the response of dissymmetric structures to electromagnetic radiation. This response can in turn reveal the arrangement of atoms in space, but deciphering the molecular information encoded in chiroptical spectra requires an effective theoretical approach. Although important correlations between ECD and molecular stereochemistry have existed for some time, a battery of accurate new theoretical methods that link a much wider range of chiroptical spectroscopies to structure have emerged over the past decade. The promise of this field is considerable: theory and spectroscopy can assist in assigning the relative and absolute configurations of complex products, revealing the structure of noncovalent aggregates, defining metrics for molecular diversity based on polarization response, and designing chirally imprinted nanomaterials. The physical organic chemistry of chirality is fascinating in its own right: defining atomic and group contributions to optical rotation (OR) is now possible. Although the common expectation is that chiroptical response is determined solely by a chiral solute's electronic structure in a given environment, chiral imprinting effects on the surrounding medium and molecular assembly can, in fact, dominate the chiroptical signatures. The theoretical interpretation of chiroptical markers is challenging because the optical properties are subtle, resulting from the strong electric dipole and the weaker electric quadrupole and magnetic dipole perturbations by the electromagnetic field. Moreover, OR arises from a combination of nearly canceling contributions to the electronic response. Indeed, the challenge posed by the chiroptical properties delayed the advent of even qualitatively accurate descriptions for some chiroptical signatures until the past decade when, for example, prediction of the observed sign of experimental OR became accessible to theory. The computation of chiroptical signatures, in close coordination with synthesis and spectroscopy, provides a powerful framework to diagnose and interpret the dissymmetry of chemical structures and molecular assemblies. Chiroptical theory now produces new schemes to elucidate structure, to describe the specific molecular sources of chiroptical signatures, and to assist in our understanding of how dissymmetry is templated and propagated in the condensed phase.

Characterizing aqueous solution conformations of a peptide backbone using Raman optical activity computations.

Mounting spectroscopic evidence indicates that alanine predominantly adopts extended polyproline II (PPII) conformations in short polypeptides. Here we analyze Raman optical activity (ROA) spectra of N-acetylalanine-N'-methylamide (Ala dipeptide) in H2O and D2O using density functional theory on Monte Carlo (MC) sampled geometries to examine the propensity of Ala dipeptide to adopt compact right-handed (alpha(R)) and left-handed (alpha(L)) helical conformations. The computed ROA spectra based on MC-sampled alpha(R) and PPII peptide conformations contain all the key spectral features found in the measured spectra. However, there is no significant similarity between the measured and computed ROA spectra based on the alpha(L)- and beta-conformations sampled by the MC methods. This analysis suggests that Ala dipeptide populates the alpha(R) and PPII conformations but no substantial population of alpha(L)- or beta-structures, despite sampling alpha(L)- and beta-structures in our MC simulations. Thus, ROA spectra combined with the theoretical analysis allow us to determine the dominant populated structures. Including explicit solute-solvent interactions in the theoretical analysis is essential for the success of this approach.

Molecular dynamics simulation of a palmitoyl-oleoyl phosphatidylserine bilayer with Na+ counterions and NaCl.

Two 40 ns molecular dynamics simulations of a palmitoyl-oleoyl phosphatidylserine (POPS) lipid bilayer in the liquid crystalline phase with Na(+) counterions and NaCl were carried out to investigate the structure of the negatively charged lipid bilayer and the effect of salt (NaCl) on the lipid bilayer structure. Na(+) ions were found to penetrate deep into the ester region of the water/lipid interface of the bilayer. Interaction of the Na(+) ions with the lipid bilayer is accompanied by a loss of water molecules around the ion and a simultaneous increase in the number of ester carbonyl oxygen atoms binding the ion, which define an octahedral and square pyramidal geometry. The amine group of the lipid molecule is involved in the formation of inter- and intramolecular hydrogen bonds with the carboxylate and the phosphodiester groups of the lipid molecule. The area per lipid of the POPS bilayer is unaffected by the presence of 0.15M NaCl. There is a small increase in the order parameter of carbon atoms in the beginning of the alkyl chain in the presence of NaCl. This is due to a greater number of Na(+) ions being coordinated by the ester carbonyl oxygen atoms in the water/lipid interface region of the POPS bilayer.

Distribution of pentachlorophenol in phospholipid bilayers: a molecular dynamics study.

Molecular dynamics computer simulations of pentachlorophenol (PCP) in palmitoyl-oleoyl-phosphatidylethanolamine and palmitoyl-oleoyl-phosphatidylcholine lipid bilayers were carried out to investigate the distribution of PCP and the effects of PCP on the phospholipid bilayer structure. Starting from two extreme starting structures, including PCP molecules outside the lipid bilayer, the PCP distribution converges in simulations of up to 50 ns. PCP preferentially occupies the region between the carbonyl groups and the double bonds in the acyl chains of the lipid molecules in the bilayer. In the presence of PCP, the lipid chain order increases somewhat in both chains, and the average tilt angle of the lipid chains decreases. The increase in the lipid chain order in the presence of PCP was more pronounced in the palmitoyl-oleoyl-phosphatidylcholine bilayer compared to the palmitoyl-oleoyl-phosphatidylethanolamine bilayer. The number of trans conformations of lipid chain dihedrals does not change significantly. PCP aligns parallel to the alkyl chains of the lipid to optimize the packing in the dense ordered chain region of the bilayer. The hydroxyl group of PCP forms hydrogen bonds with both water and lipid oxygen atoms in the water/lipid interface region.