Biomedical subjects
Publications and source records attributed to Scott L Cockroft.
The folding behaviour of the molecular torsion balance framework is rationalised by considering the effects of solvation using the alpha/beta H-bond parameter scheme for estimating the free energies of pairwise functional group interactions in solution.
A supramolecular approach has been used to investigate the free energies of intermolecular aromatic stacking interactions. Chemical double mutant cycles have been used to measure the effect of a range of substituents on face-to-face stacking interactions with phenyl and pentafluorophenyl rings. Electrostatic effects dominate the trends in interaction energy.
Chemical double mutant cycles have been used to quantify the interactions of halogens with the faces of aromatic rings in chloroform. The halogens are forced over the face of an aromatic ring by an array of hydrogen-bonding interactions that lock the complexes in a single, well-defined conformation. These interactions can also be engineered into the crystal structures of simpler model compounds, but experiments in solution show that the halogen-aromatic interactions observed in the solid state are all unfavourable, regardless of whether the aromatic rings contain electron-withdrawing or electron-donating substituents. The halogen-aromatic interactions are repulsive by 1-3 kJ mol(-1). The interactions with fluorine are slightly less favourable than with chlorine and bromine.
The apparent intrinsic clearance of 13 drugs has been determined using rat liver microsomes at three different concentrations of microsomal protein. The kinetics was studied using the in vitro half-life method. The nonspecific binding of these drugs to the microsomes was also studied under the same conditions, except for cofactor removal, using equilibrium dialysis. The intrinsic clearances are shown to be dependent on the microsomal concentration, but are approximately constant when corrected for the extent of nonspecific binding to the microsomes. The large difference between observed intrinsic clearance and unbound intrinsic clearance that exists for some compounds, particularly lipophilic bases, is highlighted. A simple model has been developed for understanding the binding of compounds to microsomes and is demonstrated to accurately predict the extent of microsomal binding at one concentration of microsomes from measurement at another. The binding of a further 25 drugs to rat liver microsomes at a microsomal concentration of 1 mg/ml was also studied, along with measurements of lipophilicity using octanol-water partition coefficients. It is shown that the extent of microsomal binding is correlated with lipophilicity, but that basic compounds show a different behavior to acidic and neutral compounds. Microsomal binding is shown to be best predicted using a model where log P is used for basic compounds, and log D(7.4) is used for acidic and neutral compounds. This model has been developed further so that the extent of binding to microsomes of any given concentration can be estimated purely from a knowledge of lipophilicity and ionization.