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121.
Barr Tivon Ronen Gabizon Bente A. Somsen Peter J. Cossar Christian Ottmann Nir London 《Chemical science》2021,12(32):10836
Electrophilic peptides that form an irreversible covalent bond with their target have great potential for binding targets that have been previously considered undruggable. However, the discovery of such peptides remains a challenge. Here, we present Rosetta CovPepDock, a computational pipeline for peptide docking that incorporates covalent binding between the peptide and a receptor cysteine. We applied CovPepDock retrospectively to a dataset of 115 disulfide-bound peptides and a dataset of 54 electrophilic peptides. It produced a top-five scoring, near-native model, in 89% and 100% of the cases when docking from the native conformation, and 20% and 90% when docking from an extended peptide conformation, respectively. In addition, we developed a protocol for designing electrophilic peptide binders based on known non-covalent binders or protein–protein interfaces. We identified 7154 peptide candidates in the PDB for application of this protocol. As a proof-of-concept we validated the protocol on the non-covalent complex of 14-3-3σ and YAP1 phosphopeptide. The protocol identified seven highly potent and selective irreversible peptide binders. The predicted binding mode of one of the peptides was validated using X-ray crystallography. This case-study demonstrates the utility and impact of CovPepDock. It suggests that many new electrophilic peptide binders can be rapidly discovered, with significant potential as therapeutic molecules and chemical probes.We developed Rosetta CovPepDock, a computational pipeline for covalent peptide docking. We showed it is highly accurate in retrospective benchmarks, and applied it prospectively to design potent and selective covalent binders of 14-3-3σ. 相似文献
122.
Present experiments in pursuit of the mass difference in the system have put a lower bound on this quantity of (at 95% C.L.). The same experiments also yield a local minimum in the log-likelihood function around , which is away from being zero. Motivated by these observations, we investigate the consequences of a possible measurement of , in the context of both the standard model and supersymmetric models with minimal flavor violation. We perform a fit of the quark mixing parameters in these theories and estimate the expected ranges of the CP asymmetries in B decays, characterized by and , the interior angles of the CKM-unitarity triangle. Based on this study, we argue that, if indeed turns out to be in its currently-favored range, this would disfavor a large class of supersymmetric models. Indeed, of all the models examined here, the best fit to the data occurs for the standard model. Received: 14 December 2000 / Published online: 23 January 2001 相似文献
123.
反射相移对Faraday电流传感器灵敏度及稳定性影响的理论分析 总被引:1,自引:0,他引:1
光学法拉第电流传感器内的反射相移能降低传感器的灵敏度与稳定性。本文对此效应给予了定量的理论分析。 相似文献