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131.
Dr. Nicolas Panel Dr. Duc Duy Vo Nour Aldin Kahlous Dr. Harald Hübner Dr. Stephanie Tiedt Dr. Pierre Matricon Dr. Jody Pacalon Dr. Oliver Fleetwood Dr. Stefanie Kampen Andreas Luttens Dr. Lucie Delemotte Prof. Jan Kihlberg Prof. Peter Gmeiner Prof. Jens Carlsson 《Angewandte Chemie (International ed. in English)》2023,62(22):e202218959
G-protein-coupled receptors (GPCRs) play important roles in physiological processes and are modulated by drugs that either activate or block signaling. Rational design of the pharmacological efficacy profiles of GPCR ligands could enable the development of more efficient drugs, but is challenging even if high-resolution receptor structures are available. We performed molecular dynamics simulations of the β2 adrenergic receptor in active and inactive conformations to assess if binding free energy calculations can predict differences in ligand efficacy for closely related compounds. Previously identified ligands were successfully classified into groups with comparable efficacy profiles based on the calculated shift in ligand affinity upon activation. A series of ligands were then predicted and synthesized, leading to the discovery of partial agonists with nanomolar potencies and novel scaffolds. Our results demonstrate that free energy simulations enable design of ligand efficacy and the same approach can be applied to other GPCR drug targets. 相似文献
132.
Yajuan Yan Dr. Ping Zhou Lurong Ding Dr. Wei Hu Prof. Dr. Wei Chen Prof. Dr. Bin Su 《Angewandte Chemie (International ed. in English)》2023,62(50):e202314588
Adoptive T lymphocyte (T cell) transfer and tumour-specific peptide vaccines are innovative cancer therapies. An accurate assessment of the specific reactivity of T cell receptors (TCRs) to tumour antigens is required because of the high heterogeneity of tumour cells and the immunosuppressive tumour microenvironment. In this study, we report a label-free electrochemiluminescence (ECL) imaging approach for recognising and discriminating between TCRs and tumour-specific antigens by imaging the immune synapses of T cells. Various T cell stimuli, including agonistic antibodies, auxiliary molecules, and tumour-specific antigens, were modified on the electrode's surface to allow for their interaction with T cells bearing different TCRs. The formation of immune synapses activated by specific stimuli produced a negative (shadow) ECL image, from which T cell antigen recognition and discrimination were evaluated by analysing the spreading area and the recognition intensity of T cells. This approach provides an easy way to assess TCR-antigen specificity and screen both of them for immunotherapies. 相似文献
133.
Alessia Mortari Natalhie Campos‐Reales Giulia Corda Nigel L. Brown Elisabeth Csöregi 《Electroanalysis》2008,20(24):2677-2684
The present work reports a new application of a protein‐based capacitive biosensor as an in vitro assay for the selectivity study of the bacterial periplasmic protein MerP and four MerP variants. The modified MerP proteins were produced by site‐directed mutagenesis of the heavy metal associated motif (HMA). The MerP and modified MerPs selectivity for copper, zinc, cadmium and mercury bivalent ions were investigated and compared. The variations in the proteins affinity were related to the primary structure of the HMA motifs. Key amino acids for copper coordination of metalloproteins that contain the metal binding sequence Gly‐Met‐Thr‐Cys‐xxx‐xxx‐Cys were identified. The results brought insights valid for Menkes and Wilson ATPases. The protein‐based capacitive biosensors were a simple and useful tool for studying structure‐activity relationships of proteins. 相似文献
134.
《Journal of Coordination Chemistry》2012,65(12):1921-1927
An anion receptor was synthesized with ferrocene as binding frame. Anion recognition can be monitored by anion complexation-induced changes in UV-vis absorption spectra. Interaction between the receptor and acetate was described on the basis of 1H NMR experiments. 相似文献
135.
《Analytical letters》2012,45(9):1665-1680
Abstract The acetylcholine (ACh) receptor protein isolated from Torpedo electric organ was incorporated into asolectin liposomes and immobilized noncovalently on the surface of a Planar Interdigitated Capacitive sensor to produce an ACh receptor-based biosensor. Capacitance of the biosensor, which was stable in buffered saline, increased rapidly when ACh was added. The response was dosedependent and specific for ACh, and the biosensor did not respond to six other neurotransmitters. Impure receptor preparations containing ACh esterase produced a smaller signal in response to ACh but showed enhanced response after inhibition of ACh esterase with diisopropylfluorophosphate. The competitive antagonist d-tubocurare, and the noncompetitive antagonist amantadine, inhibited the response of the biosensor to ACh, but a time-dependent recovery occurred upon perfusion with ACh. The irreversible antagonist α-neurotoxin inhibited the response and there was no recovery following perfusion with ACh. Thus, the pharmacologic profile of the biosensor in response to drugs closely resembled that of the nicotinic ACh receptor. 相似文献
136.
A novel unsymmetrical squaramide-linked squaraine dye(SQ) has been synthesized through squaramide 3 and semisquaraine 6. The molecular structure of SQ has been characterized by ~1H NMR,IR and MS.Due to the influence of the hydrogen bond and the solvent effect,SQ exhibits unique spectral properties compared with typical squaraine dyes.For its excellent ability of binding primary amine,SQ is a promising receptor of recognizing primary amine. 相似文献
137.
Polyvinyl chloride (PVC) based membranes using macrocyclic dithioxamide receptor (I) derived from isophthaloyl dichloride and dithioxamide have been prepared and explored as HPO42−-selective sensors. Effect of various plasticizers viz., bis(2-ethylhexyl) sebacate (DOS), dibutylphosphate (DBP), tri-n-butylphosphate (TBP), O-nitrophenyl octyl ether (NPOE), tris(2-ethylhexyl)phosphate (TEHP) and a cation excluder, tridodecylmethylammonium chloride (TDDMACl) was studied in detail and improved performance was observed at several instances. Optimum performance was observed with the membrane having (I)-PVC-TDDMACl-NPOE in the ratio 2:33:1.5:63.5 (w/w). The sensor works satisfactorily in the concentration range 1.7 × 10−6 to 1.0 × 10−2 M (detection limit 0.2 ppm) with Nernstian compliance (29.6 mV/decade of activity) at pH 8.0 with a fast response time of about 8 s. The potentiometric selectivity coefficient values as determined by the matched potential method (MPM) and the fixed interference method (FIM) indicate selective response for HPO42− in presence of interfering ions. The sensor exhibits adequate shelf life (∼2 months) with good reproducibility (S.D. ± 0.4 mV). The sensor was also used successfully in the potentiometric titration of HPO42− with Ba2+. 相似文献
138.
恶性肿瘤常用的内科治疗方法为放射治疗和化学治疗,这两种治疗方法均会造成严重的恶心和呕吐等胃肠道副反应.早期的抗呕吐药物不仅其止吐效果差,还伴有严重的锥体外系副反应.自从20世纪70年代末发现5-HT3受体与呕吐机制有关以来引,5-HT3受体及其拮抗剂的研究极为活跃,目前上市的药物有Ondansetron,Granisetron,Tropisetron和Azasertron等,还有许多药物正处于临床研究阶段。 相似文献