Discovery of BAY 2413555, First Selective Positive Allosteric Modulator of the M2 Receptor to Restore Cardiac Autonomic Balance.

Autonomic disbalance, i.e., sympathetic overactivation and parasympathetic withdrawal, is a causal driver of disease progression in heart failure.

The European Lead Factory: Results from a decade of collaborative, public-private, drug discovery programs.

The European Lead Factory (ELF) is a consortium of universities and small and medium-sized enterprises (SMEs) dedicated to drug discovery, and the pharmaceutical industry. This unprecedented consortium provides high-throughput screening, triage, and hit validation, including to non-consortium members. The ELF library was created through a novel compound-sharing model between nine pharmaceutical companies and expanded through library synthesis by chemistry-specialized SMEs.

Discovery of , a Selective CNS Penetrant Chemical Probe as Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonist.

Transient receptor potential ankyrin 1 (TRPA1) is a voltage-dependent, ligand-gated ion channel, and activation thereof is linked to a variety of painful conditions. Preclinical studies have demonstrated the role of TRPA1 receptors in a broad range of animal models of acute, inflammatory, and neuropathic pain. In addition, a clinical study using the TRPA1 antagonist GRC-17536 (Glenmark Pharmaceuticals) demonstrated efficacy in a subgroup of patients with painful diabetic neuropathy.

A lipid-dependent link between activity and oligomerization state of the M. tuberculosis SMR protein TBsmr.

TBsmr is a secondary active multidrug transporter from Mycobacterium tuberculosis that transports a plethora of compounds including antibiotics and fluorescent dyes. It belongs to the small multidrug resistance (SMR) superfamily and is structurally and functionally related to E. coli EmrE.

The key residue for substrate transport (Glu14) in the EmrE dimer is asymmetric.

Transport proteins exhibiting broad substrate specificities are major determinants for the phenomenon of multidrug resistance. The Escherichia coli multidrug transporter EmrE, a 4-transmembrane, helical 12-kDa membrane protein, forms a functional dimer to transport a diverse array of aromatic, positively charged substrates in a proton/drug antiport fashion. Here, we report (13)C chemical shifts of the essential residue Glu(14) within the binding pocket.

Transport cycle intermediate in small multidrug resistance protein is revealed by substrate fluorescence.

Efflux pumps of the small multidrug resistance family bind cationic, lipophilic antibiotics and transport them across the membrane in exchange for protons. The transport cycle must involve various conformational states of the protein needed for substrate binding, translocation, and release. A fluorescent substrate will therefore experience a significant change of environment while being transported, which influences its fluorescence properties.

Gas phase chemistry in gallium nitride CVD: Theoretical determination of the Arrhenius parameters for the first Ga-C bond homolysis of trimethylgallium.

Experimental evidence suggests that the energy of activation for the first homolytic Ga-C bond fission of GaMe3 of Ea = 249 kJ/mol, measured by Jacko and Price in a hot-wall tube reactor, is affected by surface catalytic effects. In this contribution, the rate constant for this crucial step in the gas-phase pyrolysis of GaMe3 has been calculated by variational transition state theory. By a basis set extrapolation on the MP2/cc-pVXZ level and a correlation correction from CCSD(T)/cc-pVDZ level, a theoretical "best estimate" for the bond energy of Delta H(289K) = 327.

Investigating transport proteins by solid state NMR.

Transporters form an interesting and complex class of membrane proteins. Many of them are potential drug targets due to their role in translocation of ions, small molecules and peptides across the membrane or due to their role in multidrug resistance. Hence elucidating their structure and mechanism is of great importance and may lead to a host of new drugs and methods to alter or inhibit their function.

NMR and fluorescence spectroscopy approaches to secondary and primary active multidrug efflux pumps.

Multidrug efflux pumps are found in all major transporter families. Along with a lack of three-dimensional structure information, the mechanism of drug recognition, energy coupling with drug translocation and the catalytic cycle are so far not understood. In the present study, we present first data of a fluorescence-based assay to study the pH-gradient-mediated activity of the multidrug antiporter EmrE, by co-reconstitution with the light-driven proton pump bacteriorhodopsin.