The cannabinoid CB1 receptor is a Class A G-protein coupled receptor (GPCR) that is the most widely expressed GPCR in the brain. Many GPCRs contain allosteric binding sites for endogenous and/or synthetic ligands, which are topographically distinct from the agonist-binding site, which is known as the orthosteric site. While both endogenous and synthetic ligands that act at the CB1 orthosteric site have been known for some time, compounds that act at a CB1 allosteric site have only recently been discovered. The most studied of these is 5-Chloro-3-ethyl-1H-indole-2-carboxylic acid [2-(4-piperidin-1-ylphenyl)ethyl]amide (Org27569). Because allosteric ligands are thought to act through conformational changes in the receptor that are transmitted from the allosteric to the orthosteric site, computational studies of the structural and dynamic interactions of Org27569 with the CB1 receptor are crucial to achieve a molecular level understanding of the basis of action of this important new class of compounds. To date, such computational studies have not been possible due to the lack of a complete set of molecular mechanics force field parameters for Org27569. Here we present the development of missing CHARMM force field parameters for Org27569 using previously published methods and the validation and application of these new parameters using normal mode analysis and molecular dynamics simulations combined with experimental IR measurements.

Polymorphism in hybrid inorganic-organic materials has not been explored as extensively as that in organic compounds, yet differences in solid-state structure can significantly affect the physical properties central to application of these materials. A new polymorph of Ni(en) 3 MoS 4 (en = ethylenediamine), a hydrodesulfurization catalyst precursor, has been synthesized solvothermally and structurally characterized by single-crystal X-ray diffraction. The new structure (2) assumes the orthorhombic Pcab space group with a=14.020(5) A ˚, b=14.821(7) A ˚, and c=16.230(6) A ˚. The structure of a polymorph that had been found previously (1) was redetermined at 100 K, confirming the orthorhombic Pna2 1 structure with a=15.916(13) A ˚, b=7.610(3) A ˚, and c=14.093(6) A ˚. Solvothermal reaction conditions including temperature, solvent water content, and nickel source were important in controlling polymorph formation. Differential scanning calorimetry and solvent-mediated conversion studies were used to compare the stabilities of the two nickel-containing polymorphs. The system was characterized as enantiotropic, with 2 favored at ambient temperature and 1 favored at 120 °C. However, kinetic factors are influential in the intermediate temperature range, and conversion is kinetically hindered under certain conditions. The new structures Co-(en) 3 MoS 4 (3) and Mn(en) 3 MoS 4 (4) were determined through single-crystal methods to be isostructural to 2. Compounds 1-4 were also characterized by elemental analysis, infrared spectroscopy, variable-temperature magnetic susceptibility measurements, and thermogravimetric analysis.

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higher dimensional space. The grouping of cells (data points) having similar features, which is referred to as gating, is usually done manually by an expert. We developed software that performs efficient unsupervised gating determining the number of clusters, and the points belonging to each cluster. The program analyses the cross-sections of the histogram created from the data points. The method is particularly efficient in the case of large number of data points such as 10 4 -10 6 . The overall run time for the composite steps of the algorithm increases linearly by the number of data points. In our example 1 million data points, shown in the left part of the figure, were analyzed within 6 seconds on a standard laptop PC. The analysis resulted in 20 clusters, shown in the right side of the figure. The code number of the largest cluster is 1, the second largest is 2, etc.