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Photochemistry of ketones adsorbed on size/shape selective zeolites. A supramolecular approach to persistent carbon centered radicals
2H NMR, EPR, computational and product analyses of the photolysis of 2,4-diphenylpentan-3-one (DPP) adsorbed on MFI size/shape selective zeolites are consistent with supramolecular structural changes as a function of surface coverage that provide a novel method for the generation of persistent diffusing organic free radicals
Synchronous or Asynchronous? An âExperimentalâ Transition State from a Direct Comparison of Experimental and Theoretical Kinetic Isotope Effects for a DielsâAlder Reaction
[5,5] Sigmatropic Rearrangement. DFT Prediction of a Diradical Mechanism for a WoodwardâHoffmann âAllowedâ Thermal Pericyclic Reaction
Experimental Determination of the Activation Parameters and Stereoselectivities of the Intramolecular DielsâAlder Reactions of 1,3,8-Nonatriene, 1,3,9-Decatriene, and 1,3,10-Undecatriene and Transition State Modeling with the Monte Carlo-Jumping Between Wells/Molecular Dynamics Method
A Becke3LYP/6-31G* Study of the Cope Rearrangements of Substituted 1,5-Hexadienes Provides Computational Evidence for a Chameleonic Transition State
Resistance profile of the HIV-1 maturation inhibitor GSK3532795 in vitro and in a clinical study.
GSK3532795 (formerly BMS955176) is a second-generation maturation inhibitor (MI) that progressed through a Phase 2b study for treatment of HIV-1 infection. Resistance development to GSK3532795 was evaluated through in vitro methods and was correlated with information obtained in a Phase 2a proof-of-concept study in HIV-1 infected participants. Both low and high concentrations of GSK3532795 were used for selections in vitro, and reduced susceptibility to GSK3532795 mapped specifically to amino acids near the capsid/ spacer peptide 1 (SP1) junction, the cleavage of which is blocked by MIs. Two key substitutions, A364V or V362I, were selected, the latter requiring secondary substitutions to reduce susceptibility to GSK3532795. Three main types of secondary substitutions were observed, none of which reduced GSK3532795 susceptibility in isolation. The first type was in the capsid C-terminal domain and downstream SP1 region (including (Gag numbering) R286K, A326T, T332S/N, I333V and V370A/M). The second, was an R41G substitution in viral protease that occurred with V362I. The third was seen in the capsid N-terminal domain, within the cyclophilin A binding domain (V218A/M, H219Q and G221E). H219Q increased viral replication capacity and reduced susceptibility of poorly growing viruses. In the Phase 2a study, a subset of these substitutions was also observed at baseline and some were selected following GSK35323795 treatment in HIV-1-infected participants
Orthogonal Mass Spectrometry-Based Footprinting for Epitope Mapping and Structural Characterization: The ILâ6 Receptor upon Binding of Protein Therapeutics
Higher-order
structure (HOS) is a crucial determinant for the biological
functions and quality attributes of protein therapeutics. Mass spectrometry
(MS)-based protein footprinting approaches play an important role
in elucidating the relationship between protein biophysical properties
and structure. Here, we describe the use of a combined method including
hydrogenâdeuterium exchange (HDX), fast photochemical oxidation
of proteins (FPOP), and site-specific carboxyl group footprinting
to investigate the HOS of protein and protein complexes. The work
focuses on implementing complementary solution-phase footprinting
approaches that differ in time scale, specificity for protein residue
side chains vs backbone as well as selectivity for different residue
types to map integratively the epitope of human interleukin-6 receptor
(IL-6R) for two adnectins with distinct affinities (<i>K</i><sub>d, Adnectin1</sub> ⌠6.2 pM vs <i>K</i><sub>d, Adnectin2</sub> ⌠46 nM). Furthermore, the study
evaluates the resultant conformation/dynamic change of IL-6R. The
suggested epitope, which is conserved for adnectin1 and adnectin2
binding, is a flexible loop that connects two ÎČ-strands in the
cytokine-binding domain (DII) of IL-6R. We also found that adnectin1,
the more strongly binding ligand, induces structural perturbations
on two unstructured loops that are distally located beyond the epitope.
Those changes are either attenuated or not detected for the case of
adnectin2 binding. In addition to providing credibility in epitope
determination, utilization of those combined approaches reveals the
structural effects that can differentiate protein therapeutics with
apparently similar biophysical properties