Relative reactivity of alkenyl alcohols in the palladium-catalyzed redox-relay Heck reaction

The relative rates of alkenyl alcohols in the Pd-catalyzed redox-relay Heck reaction were measured in order to examine the effect of their steric and electronic properties on the rate-determining step. Competition experiments between an allylic alkenyl alcohol and two substrates with differing chain lengths revealed that the allylic alcohol reacts 3–4 times faster in either case. Competition between di- and trisubstituted alkenyl alcohols provided an interesting scenario, in which the disubstituted alkene was consumed first followed by reaction of the trisubstituted alkene. Consistent with this observation, the transition structures for the migratory insertion of the aryl group into the di- and trisubstituted alkenes were calculated with a lower barrier for the former. An internal competition between a substrate containing two alcohols with differing chain lengths demonstrated the catalyst's preference for migrating toward the closest alcohol. Additionally, it was observed that increasing the electron-density in the arene boronic acid promotes a faster reaction, which correlates with Hammett [sigma-rho] values to give a [rho] of −0.87

SET-Induced Biaryl Cross-Coupling: An S_RN1 Reaction

The SET-induced biaryl cross-coupling reaction is established as the first example of a Grignard S_RN1 reaction. The reaction is examined within the mechanistic framework of dissociative electron transfer in the presence of a Lewis acid. DFT calculations show that the reaction proceeds through a radical intermediate in the form of an Mg ion-radical cage, which eludes detection in trapping experiments by reacting quickly to form an MgPh₂ radical anion intermediate. A new mechanism is proposed

Computational Exploration of Zinc Binding Groups for HDAC Inhibition

Histone deacetylases (HDACs) have emerged as important drug targets in epigenetics. The most common HDAC inhibitors use hydroxamic acids as zinc binding groups despite unfavorable pharmacokinetic properties. A two-stage protocol of M05-2X calculations of a library of 48 fragments in a small model active site, followed by QM/MM hybrid calculations of the full enzyme with selected binders, is used to prospectively select potential bidentate zinc binders. The energetics and interaction patterns of several zinc binders not previously used for the inhibition of HDACs are discussed

Understanding Rate Acceleration and Stereoinduction of an Asymmetric Giese Reaction Mediated by a Chiral Rhodium Catalyst

The surprising acceleration of the addition of electron-rich radicals to α,β-unsaturated 2-acyl imidazoles by a chiral-at-metal rhodium catalyst is investigated. M06/Lanl2DZ (Rh),6-31G­(d) calculations reproduce the observed rate acceleration and shed light on a catalyst design where a rigid chiral pocket with a steric interaction >5 Å from the chiral metal center leads to the observed high stereoinduction. Analysis of the molecular orbitals of two key addition transition states emphasize the role of the catalyst as a Lewis acid without significant charge transfer

Computational Exploration of Zinc Binding Groups for HDAC Inhibition

Histone deacetylases (HDACs) have emerged as important drug targets in epigenetics. The most common HDAC inhibitors use hydroxamic acids as zinc binding groups despite unfavorable pharmacokinetic properties. A two-stage protocol of M05-2X calculations of a library of 48 fragments in a small model active site, followed by QM/MM hybrid calculations of the full enzyme with selected binders, is used to prospectively select potential bidentate zinc binders. The energetics and interaction patterns of several zinc binders not previously used for the inhibition of HDACs are discussed

Computational Exploration of Zinc Binding Groups for HDAC Inhibition

Histone deacetylases (HDACs) have emerged as important drug targets in epigenetics. The most common HDAC inhibitors use hydroxamic acids as zinc binding groups despite unfavorable pharmacokinetic properties. A two-stage protocol of M05-2X calculations of a library of 48 fragments in a small model active site, followed by QM/MM hybrid calculations of the full enzyme with selected binders, is used to prospectively select potential bidentate zinc binders. The energetics and interaction patterns of several zinc binders not previously used for the inhibition of HDACs are discussed

Computational Exploration of Zinc Binding Groups for HDAC Inhibition

Histone deacetylases (HDACs) have emerged as important drug targets in epigenetics. The most common HDAC inhibitors use hydroxamic acids as zinc binding groups despite unfavorable pharmacokinetic properties. A two-stage protocol of M05-2X calculations of a library of 48 fragments in a small model active site, followed by QM/MM hybrid calculations of the full enzyme with selected binders, is used to prospectively select potential bidentate zinc binders. The energetics and interaction patterns of several zinc binders not previously used for the inhibition of HDACs are discussed

Computational Exploration of Zinc Binding Groups for HDAC Inhibition

Histone deacetylases (HDACs) have emerged as important drug targets in epigenetics. The most common HDAC inhibitors use hydroxamic acids as zinc binding groups despite unfavorable pharmacokinetic properties. A two-stage protocol of M05-2X calculations of a library of 48 fragments in a small model active site, followed by QM/MM hybrid calculations of the full enzyme with selected binders, is used to prospectively select potential bidentate zinc binders. The energetics and interaction patterns of several zinc binders not previously used for the inhibition of HDACs are discussed

Computational Exploration of Zinc Binding Groups for HDAC Inhibition

Histone deacetylases (HDACs) have emerged as important drug targets in epigenetics. The most common HDAC inhibitors use hydroxamic acids as zinc binding groups despite unfavorable pharmacokinetic properties. A two-stage protocol of M05-2X calculations of a library of 48 fragments in a small model active site, followed by QM/MM hybrid calculations of the full enzyme with selected binders, is used to prospectively select potential bidentate zinc binders. The energetics and interaction patterns of several zinc binders not previously used for the inhibition of HDACs are discussed

Computational Studies of the Cholesterol Transport between NPC2 and the N‑Terminal Domain of NPC1 (NPC1(NTD))

The transport of cholesterol from NPC2 to NPC1 is essential for the maintenance of cholesterol homeostasis in late endosomes. On the basis of a rigid docking model of the crystal structures of the N-terminal cholesterol binding domain of NPC1­(NTD) and the soluble NPC2 protein, models of the NPC1­(NTD)-NPC2-cholesterol complexes at the beginning and the end of the transport as well as the unligated NPC1­(NTD)-NPC2 complex were studied using 86 ns MD simulations. Significant differences in the cholesterol binding mode and the overall structure of the two proteins compared to the crystal structures of the cholesterol binding separate units were obtained. Relevant residues for the binding are identified using MM/GBSA calculations and the influence of the mutations analyzed by modeling them <i>in silico</i>, rationalizing the results of previous mutagenesis experiments. From the calculated energies and the NEB (nudged elastic band) evaluation of the cholesterol transfer mechanism, an atomistic model is proposed of the transfer of cholesterol from NPC2 to NPC1­(NTD) through the formation of an intermediate NPC1­(NTD)-NPC2 complex