Free energies of binding of R- and S-propranolol to wild-type and F483A mutant cytochrome P450 2D6 from molecular dynamics simulations

Detailed molecular dynamics (MD) simulations have been performed to reproduce and rationalize the experimental finding that the F483A mutant of CYP2D6 has lower affinity for R-propranolol than for S-propranolol. Wild-type (WT) CYP2D6 does not show this stereospecificity. Four different approaches to calculate the free energy differences have been investigated and were compared to the experimental binding data. From the differences between calculations based on forward and backward processes and the closure of thermodynamic cycles, it was clear that not all simulations converged sufficiently. The approach that calculates the free energies of exchanging R-propranolol with S-propranolol in the F483A mutant relative to the exchange free energy in WT CYP2D6 accurately reproduced the experimental binding data. Careful inspection of the end-points of the MD simulations involved in this approach, allowed for a molecular interpretation of the observed differences

Mercury(II)-mediated routes to some side-chain functionalised 1,7-dioxaspiro[5.5]undecanes. Applications of Luche-Barbier chemoselective addition to ketoaldehydes

The ketoaldehyde, 5-oxo-9-decenal (4) undergoes chemoselective addition to the aldehyde with either allyl or propargyl bromide under Luche-Barbier conditions. Oxymercuration-cyclisation of the resulting hydroxyketones, followed by reductive or oxidative demercuration, provides functionalised spiroacetals, some of which are of insect origin

Stereoselective synthesis, natural occurrence and CB₂ receptor binding affinities of alkylamides from herbal medicines such as 'Echinacea' sp.

A divergent synthesis of (2E,4E,8E,10E)- and (2E,4E,8E,10Z)-N-isobutyldodeca-2,4,8,10-tetraenamides from pent-4-yn-1-ol allowed identification of the (2E,4E,8E,10Z)-isomer for the first time in Echinacea species. A short, stereoselective synthesis of the (2E,4E,8E,10Z)-isomer is also described which allowed further biological evaluation of this material, and the demonstration that this isomer does not occur in 'Spilanthes mauritiana' as previously reported