The effects of resistant starch and whole grains on appetite, food intake and metabolic response.

With the rise in obesity, there has been an increased interest in foods which may beneficially affect appetite. Resistant starch (RS) and whole grains (of which RS is a main dietary fibre component) have been proposed to affect satiety and therefore may be beneficial in weight management. There is little direct evidence confirming this in humans. Whilst animal data suggest a positive effect of RS on appetite, the few existing human intervention studies provide inconsistent findings. For whole grains the majority of evidence is from epidemiological work as opposed to intervention studies. Therefore a series of studies was conducted to investigate effects of RS and whole grains on appetite and food intake. Two studies were conducted using RS. The first investigated the acute (24 hours) effects of 48 g RS in healthy adult males compared with an energy and available carbohydrate matched placebo. Following RS there was a significantly lower energy intake compared with placebo. There was also a significantly lower postprandial insulin response with RS, possibly explained by increased hepatic insulin clearance determined by a higher C-peptide to insulin ratio. In the second study 40 g RS consumed daily for 4 weeks was compared with the placebo, in overweight and obese participants. Effects on food intake were assessed and a frequently sampled intravenous glucose tolerance test (FSIVGTT) was conducted. This study found no effect on either appetite or energy intake, but did find significantly higher glucose, insulin and C-peptide concentrations, measured during the FSIVGTT, with the RS compared with the placebo, possibly explained by an improved first-phase insulin response. This finding did not translate into differences in parameters obtained from modelling the FSIVGTT data, but this and the lack of appetite and food intake differences could be explained by the small participant numbers. Two intervention studies were conducted with whole grains incorporated into bread rolls. The first, a crossover study, involved 3 weeks' daily consumption of 48 g milled whole grain or control, in young healthy adults. Whilst no significant difference was found between interventions in energy intake or subjective appetite ratings, a significantly lower systolic blood pressure was observed with the milled whole grains. The second was an 8 week parallel study (48 g intact or 48 g milled whole grains or control) in overweight and obese adults. No significant difference was found between groups on energy intake, subjective appetite ratings, cholesterol or postprandial metabolite concentrations. RS appears to be a possible satiating ingredient when consumed acutely and, whilst this was not confirmed in our chronic study, effects may have been masked by small participant numbers. A novel finding from our RS studies was an effect on the insulin response. These studies suggest that RS could have a beneficial role in weight management and favourable metabolic effects. Our whole grain interventions appear not to agree with epidemiological work that suggests a beneficial role on appetite, but there maybe effects on blood pressure regulation. In all instances further investigations are required in other population groups, with more participants and for longer time periods

Toward Fully Automated High Performance Computing Drug Discovery: A Massively Parallel Virtual Screening Pipeline for Docking and Molecular Mechanics/Generalized Born Surface Area Rescoring to Improve Enrichment

In this work we announce and evaluate a high throughput virtual screening pipeline for <i>in-silico</i> screening of virtual compound databases using high performance computing (HPC). Notable features of this pipeline are an automated receptor preparation scheme with unsupervised binding site identification. The pipeline includes receptor/target preparation, ligand preparation, VinaLC docking calculation, and molecular mechanics/generalized Born surface area (MM/GBSA) rescoring using the GB model by Onufriev and co-workers [<i>J. Chem. Theory Comput.</i> <b>2007</b>, <i>3</i>, 156–169]. Furthermore, we leverage HPC resources to perform an unprecedented, comprehensive evaluation of MM/GBSA rescoring when applied to the DUD-E data set (Directory of Useful Decoys: Enhanced), in which we selected 38 protein targets and a total of ∼0.7 million actives and decoys. The computer wall time for virtual screening has been reduced drastically on HPC machines, which increases the feasibility of extremely large ligand database screening with more accurate methods. HPC resources allowed us to rescore 20 poses per compound and evaluate the optimal number of poses to rescore. We find that keeping 5–10 poses is a good compromise between accuracy and computational expense. Overall the results demonstrate that MM/GBSA rescoring has higher average receiver operating characteristic (ROC) area under curve (AUC) values and consistently better early recovery of actives than Vina docking alone. Specifically, the enrichment performance is target-dependent. MM/GBSA rescoring significantly out performs Vina docking for the folate enzymes, kinases, and several other enzymes. The more accurate energy function and solvation terms of the MM/GBSA method allow MM/GBSA to achieve better enrichment, but the rescoring is still limited by the docking method to generate the poses with the correct binding modes

Cartoon representation of the relative free energy for CYP2A6-APAP metabolism according to the Curtin-Hammett principle.

<p>Cartoon representation of the relative free energy for CYP2A6-APAP metabolism according to the Curtin-Hammett principle.</p

Top 5 (#1–5) scoring binding poses from CYP2E1-APAP docking results.

<p>Orientation of the views has been kept the same for easy comparison.</p

Docking and MD results for CYP3A4-APAP.

<p>(a) CYP3A4-APAP docking poses feature close proximity of NH-O1 (left) and OH-O1 (right), carbon atoms of the heme and the iron coordinating cysteine residue are colored in cyan, carbon atoms of APAP are colored in purple, iron is shown as a sphere and color in lime (the same color schemes are also used for all other figures). (b) APAP poses identified from MD simulation trajectories, featuring close proximity of NH-O1 (left) and OH-O1 (middle), and close proximity of the C-3 atom to O1 but with no proximity of either NH-O1 or OH-O1 (right). (c) Distribution of RC1 and RC2 in all 15 MD simulations of CYP3A4-APAP with the S1, S2, and S3 states defined. (d) Distribution of RC1 and RC2 for all USP windows.</p

Schematic representation of acetaminophen metabolism by cytochrome P450s.

<p>Schematic representation of acetaminophen metabolism by cytochrome P450s.</p

Free energy profiles for CYP-APAP binding.

<p>(a) CYP3A4, (b) CYP2E1, (c) CYP2A6, (d) CYP1A2, (e) CYP2C9. Topography energy legend with energy values (kcal/mol) represented by defined color is given in (f). Binding states, S1, S2, S3, S1r and SD are labeled. For CYP2E1, CYP2A6, and CYP1A2, the binding states are clearly defined as energy basins. For CYP3A4 and CYP2C9 where the energy landscape is relatively flat, energy profiles with more color layers are given Figure S4 in Figure S1.</p

Active site snapshots of CYP2C9-APAP.

<p>(a) S1, (b) S2, (c) S3, (d) SD states.</p

Active site snapshots of CYP2A6-APAP.

<p>(a) S1, (b) S1r, (c) S2, (d) S3 states.</p

APAP-CYPs regioselectivity determined by experimental data and calculation.

#<p>Empirical TS barrier different refers to the estimated energy difference between <i>N-</i>oxidation and 3<i>-C</i>-hydroxylation from CYP2A6 study.</p>*<p>Both S2 and S3 could lead to 3-OH-APAP. NAPQI could be slightly favored product.</p