Coupling enhanced sampling of the apo-receptor with template-based ligand conformers selection: performance in pose prediction in the D3R Grand Challenge 4.

We report the performance of our newly introduced Ensemble Docking with Enhanced sampling of pocket Shape (EDES) protocol coupled to a template-based algorithm to generate near-native ligand conformations in the 2019 iteration of the Grand Challenge (GC4) organized by the D3R consortium. Using either AutoDock4.2 or HADDOCK2.2 docking programs (each software in two variants of the protocol) our method generated native-like poses among the top 5 submitted for evaluation for most of the 20 targets with similar performances. The protein selected for GC4 was the human beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), a transmembrane aspartic-acid protease. We identified at least one pose whose heavy-atoms RMSD was less than 2.5 Å from the native conformation for 16 (80%) and 17 (85%) of the 20 targets using AutoDock and HADDOCK, respectively. Dissecting the possible sources of errors revealed that: (i) our EDES protocol (with minor modifications) was able to sample sub-ångstrom conformations for all 20 protein targets, reproducing the correct conformation of the binding site within ~ 1 Å RMSD; (ii) as already shown by some of us in GC3, even in the presence of near-native protein structures, a proper selection of ligand conformers is crucial for the success of ensemble-docking calculations. Importantly, our approach performed best among the protocols exploiting only structural information of the apo protein to generate conformations of the receptor for ensemble-docking calculations.

[Effects of low calorie sweeteners based on data from clinical trials, in vitro and animal studies]. / Az energiamentes édesítoszerek alkalmazásának hatása klinikai vizsgálatok, in vitro és állatkísérletek eredményei alapján.

Low calorie sweeteners are used by many consumers as they can provide the sweet taste without calories and, therefore, they may have a beneficial effect on weight management. These positive outcomes are often questioned and accused of keeping up or increasing a liking for sweetness and leading to overconsumption of sugar containing food and beverages. The most recent studies failed to find any positive correlation between usage of low calorie sweeteners and craving for sweet taste. In randomized controlled trials consumption of low calorie sweeteners have accompanied with lower intake of sugar containing food, higher healthy eating index and better weight management. Several laboratory trials on cell cultures and animal studies found a link between the usage of low calorie sweeteners and positive metabolic effects, e.g. smaller ectopic fat deposits in the fat and liver tissue versus controll group. In addition, increased adipogenesis and reduction of lipolysis were also observed. Orv. Hetil., 2016, 157(Suppl. 1), 3-7.

Stereoselective endocrine-disrupting effects of the chiral triazole fungicide prothioconazole and its chiral metabolite.

The wide use of chiral fungicides has generated interest in the stereoselectivity of their ecotoxicological effects. However, there are few studies about the potential endocrine-disrupting effects (EDEs) of chiral fungicides. This study evaluated the hormone receptor activities of the chiral triazole fungicide prothioconazole and its metabolite using reporter gene assays. The results indicated that prothioconazole and its metabolite possessed EDEs, and the metabolite exerted more activities than the activities of the parent compound, suggesting that the metabolic process is toxification. Stereoselective EDEs were observed, and the S-enantiomers possessed greater hormonal effects than those possessed by the R-enantiomers; the REC20 values ranged from 7.9 × 10-10 to 6.4 × 10-7 M for the thyroid hormone effects and from 3.2 × 10-9 to 7.8 × 10-8 M for the estrogenic effects. The molecular docking results revealed that the stereoselective EDEs of prothioconazole and its metabolite were partially attributed to enantiospecific receptor binding affinities. Overall, our results reveal that prothioconazole and its metabolite might disrupt the balance of the endocrine system by affecting the function of multiple nuclear hormone receptors and that they have the potential to affect the developmental and reproductive systems in humans.

Drug-eluting biostable and erodible stents.

This paper reviews the latest research and development of drug-eluting stents. The emphasis is on coronary stenting, and both biostable and bioerodible stents are covered in this review. The advantages and shortcomings of the bioactive molecules used in these stents are analyzed, along with the rationale for using bioerodible coatings. The overall emphasis is on the performance of these stents in the clinic. Based on the evaluation of the different stent types, we conclude that fully-erodible stents with a coating of antiproliferative drug will slowly gain market share in the near future, and that the search for a more selective anti-proliferative compound will continue. Dual-drug eluting stents (DDESs) will have their market share but possibly a much smaller one than that for single-drug eluting stents due to the complexities and costs of DDES unless significantly superior performance is demonstrated in the clinic.