Development and validation of European guidelines for seismic qualification of post-installed anchors.

This paper presents the technical background for the seismic qualification procedures for post-installed anchors in the European Technical Approval Guideline (ETAG 001) seismic annex issued in 2013. We discuss requirements for a comprehensive guideline and reference supporting documentation. Numerical studies to generate new simulated seismic protocols for anchors are summarized with focus on their application to Europe. To reduce the time and cost of anchor product qualification testing while fulfilling the requirement of European building codes to assess two performance categories, we combine the results of our numerical studies to generate novel testing protocols that allow for the assessment of anchor behavior at multiple levels in a unified protocol. Validation tests demonstrate that the unified protocol results in anchor performance comparable with that achieved in multiple, single-performance-level tests.

Evaluation of Density Functionals, SCC-DFTB, Neglect of Diatomic Differential Overlap (NDDO) Models and Molecular Mechanics Methods for Prolyl-Leucyl-Glycinamide (PLG) and Structural Derivatives.

Prolyl-leucyl-glycinamide (PLG) is a unique endogenous peptide that modulates dopamine receptor subtypes of the D(2) receptor family within the CNS. We seek to elucidate the structural basis and molecular mechanism by which PLG and its analogues modulate dopamine receptors, toward the development of new therapeutics to treat Parkinson's disease, tardive dyskinesia and schizophrenia. As a first step toward establishing a validated protocol for accurate computational modeling of PLG and associated peptidomimetic analogues, we evaluated the accuracy of density functional theory (DFT), wavefunction theory (WFT), and molecular mechanics (MM) calculations for PLG and for a library of structurally related small molecules. We first tested twelve local and nonlocal density functionals, Hartree-Fock (HF) theory, four "semiempirical" methods of the neglect of diatomic differential overlap (NDDO) type, and one self-consistent-charge nonorthogonal tight-binding (SCC-DFTB) method as implemented in two software suites, against coupled-cluster benchmark geometries for 4-methylthiazolidine, a small molecule that comprises key structural features present in our PLG analogue library. DFT and HF calculations were done with the MG3S augmented polarized triple-zeta basis set. We find that for 4-methylthiazolidine bond distances, DFT significantly outperforms NDDO, and both SCC-DFTB versions we evaluated perform worse than HF theory and are less accurate than 83% of the density functionals tested. The top five functionals for 4-methylthiazolidine were M05-2X, mPW1PW, B97-2, M06-2X, and PBEh, with mean unsigned errors (MUEs) in bond length of 0.0017, 0.0020, 0.0023, 0.0025 and 0.0027 Å, respectively. The widely used B3LYP functional ranked 11(th) out of twelve functionals evaluated, slightly below SCC-DFTB, and is significantly less accurate for 4-methylthiazolidine bond distances (MUE = 0.0095 Å) than the best local functional (M06-L, MUE = 0.0030 Å), which is far less computationally costly. Based on that initial analysis, we obtained new M05-2X benchmark geometric parameters for PLG and a library of eleven peptidomimetic derivatives, which we in turn used to examine the accuracy of thirty-four popular molecular mechanics (MM) force fields, four NDDO approaches, and SCC-DFTB for the full compound structures. Here, we found that ∼70% of the MM force fields tested superior to the best semiempirical and SCC-DFTB codings. Moreover, AMBER-type force fields proved most accurate among MM methods for this class of small-molecule peptidomimetics; the AMBER-type methods comprised eight out of the top ten molecular mechanics options we tested.

Functional pharmacology of human prostanoid EP2 and EP4 receptors.

Prostanoid EP(2) and EP(4) receptor-mediated responses are difficult to distinguish pharmacologically because of the lack of potent, selective antagonists. We describe systematic agonist fingerprints for recombinant human prostanoid EP(2) and EP(4) receptors expressed in CHO and HEK293 cells, respectively. The rank orders of potency of endogenous prostaglandins were: prostanoid EP(2) receptors: prostaglandin E(2)>>prostaglandin D(2)=prostaglandin F(2alpha)>prostaglandin I(2); prostanoid EP(4) receptors: prostaglandin E(2)>>prostaglandin I(2)>prostaglandin D(2)=prostaglandin F(2alpha). Butaprost free acid (9-oxo-11alpha,16R-dihydroxy-17-cyclobutyl-prost-13E-en-1-oic acid) behaved as a highly selective partial agonist at prostanoid EP(2) receptors while butaprost methyl ester elicited small, low potency responses. The prostanoid EP(1) and EP(3) receptor agonists misoprostol (9-oxo-11alpha,16-dihydroxy-16-methyl-prost-13E-en-1-oic acid, methyl ester), sulprostone (N-(methylsulphonyl)-9-oxo-11alpha,15R-dihydroxy-16-phenoxy-17,18,19,20-tetranor-prosta-5Z,13E-dien-1-amide), and GR63799X ([1R-[1alpha(Z),2beta(R*),3alpha]-(-)-4-benzoylamino)phenyl-7-[3-hydroxy-3-phenoxy-propoxy)-5-oxocyclopentyl]-4-heptenoate), and the prostanoid DP receptor agonist BW245C ((4S)-(3-[(3R,S)-3-cyclohexyl-3-hydropropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid), activated both prostanoid EP(2) and EP(4) receptors. Prostaglandin I(2), iloprost (6,9alpha-methylene-11alpha,15S-dihydroxy-16-methyl-prosta-5E,13E-dien-18-yn-1-oic acid, trometamol salt) and cicaprost (5-[(E)-(1S, 5S, 6S, 7R)-7-hydroxy-6-[(3S, 4S)-3-hydroxy-4-methylnona-1,6-diinyl]-bicyclo[3.3.0]octan-3-yliden]-3-oxapentanoic acid; ZK96480) were full agonists at prostanoid EP(4) receptors. Key differentiating agonists are: butaprost FA, 16,16-dimethyl-prostaglandin E(2), 19-(R)-hydroxy prostaglandin E(2), misoprostol, BW245C, prostaglandin F(2alpha) and prostaglandin D(2).