Design Novel Dual Agonists for Treating Type-2 Diabetes by Targeting Peroxisome Proliferator-Activated Receptors with Core Hopping Approach

Owing to their unique functions in regulating glucose, lipid and cholesterol metabolism, PPARs (peroxisome proliferator-activated receptors) have drawn special attention for developing drugs to treat type-2 diabetes. By combining the lipid benefit of PPAR-alpha agonists (such as fibrates) with the glycemic advantages of the PPAR-gamma agonists (such as thiazolidinediones), the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence has become a promising strategy for designing effective drugs against type-2 diabetes. In this study, by means of the powerful “core hopping” and “glide docking” techniques, a novel class of PPAR dual agonists was discovered based on the compound GW409544, a well-known dual agonist for both PPAR-alpha and PPAR-gamma modified from the farglitazar structure. It was observed by molecular dynamics simulations that these novel agonists not only possessed the same function as GW409544 did in activating PPAR-alpha and PPAR-gamma, but also had more favorable conformation for binding to the two receptors. It was further validated by the outcomes of their ADME (absorption, distribution, metabolism, and excretion) predictions that the new agonists hold high potential to become drug candidates. Or at the very least, the findings reported here may stimulate new strategy or provide useful insights for discovering more effective dual agonists for treating type-2 diabetes. Since the “core hopping” technique allows for rapidly screening novel cores to help overcome unwanted properties by generating new lead compounds with improved core properties, it has not escaped our notice that the current strategy along with the corresponding computational procedures can also be utilized to find novel and more effective drugs for treating other illnesses

Short- and long-term outcomes of single bare metal stent versus drug eluting stent in nondiabetic patients with a simple de novo lesion in the middle and large vessel

<p>Abstract</p> <p>Objective</p> <p>This study was aimed to investigate the short- and long-term outcomes of percutaneous coronary intervention (PCI) between single bare metal stent (BMS) and single drug eluting stent (DES) in nondiabetic patients with a simple de novo lesion in the middle and large vessel.</p> <p>Methods</p> <p>Two hundred and thirty-five consecutive patients with a simple de novo lesion in the middle and large vessel were treated with BMS or DES in our hospital from Apr. 2004 to Dec. 2004.</p> <p>The inclusion criteria: a simple de novo lesion in the middle and large vessel, stent diameter ≥ 3.0 mm, stent length ≤ 18 mm, the exclusion criteria: diabetes mellitus, left main trunk disease and left ventricular ejection fraction ≤ 30%. Of them, there were 150 patients in BMS group and 85 patients in DES group, and the rates of lost to follow up were 6.7% and 1.2% respectively.</p> <p>Results</p> <p>BMS group had lower hypercholesteremia rate (22.0% vs 38.8%) and higher proportion of TIMI grade 0 (12% vs 1.2%) than DES group (all P < 0.05), but both groups had similar stent length (16.16 ± 2.81 mm vs 16.06 ± 2.46 mm) and stent diameter (3.85 ± 3.07 mm vs 3.19 ± 0.24 mm) after procedure, in-segment restenosis rate (0% vs 1.2%) and target lesion revascularization (TLR, 2.0% vs 2.4%) at 6-month follow-up (all P > 0.05). No difference was found in TLR (1.3% vs 1.2%, P = 1.00) and recurrent myocardial infarction (Re-MI) (0% vs 1.2%, P = 0.36), cardiac death (0.7% vs 1.2%, P = 1.00) between 1- and 3-year. So were TLR (6.0% vs 5.9%, P = 0.97), Re-MI (0% vs 2.4%, P = 0.06), cardiac death (2.0% vs 3.5%, P = 0.48) and major adverse cardiac events (MACE, 8.7% vs 10.6%, P = 0.63), cardiac death-free cumulative survival (98.7% vs 97.7%, P = 0.56), TLR-free cumulative survival (94.0% vs 94.1%, P = 0.98) and Re-MI-free cumulative survival (100% vs 97.7%, P = 0.06) at 3-year follow-up.</p> <p>Conclusion</p> <p>The single BMS has similar efficacy and safety to single DES in nondiabetic patients with a simple de novo lesion in the middle and large vessel at short- and long-term follow-up.</p

Novel Inhibitor Design for Hemagglutinin against H1N1 Influenza Virus by Core Hopping Method

The worldwide spread of H1N1 avian influenza and the increasing reports about its resistance to the current drugs have made a high priority for developing new anti-influenza drugs. Owing to its unique function in assisting viruses to bind the cellular surface, a key step for them to subsequently penetrate into the infected cell, hemagglutinin (HA) has become one of the main targets for drug design against influenza virus. To develop potent HA inhibitors, the ZINC fragment database was searched for finding the optimal compound with the core hopping technique. As a result, the Neo6 compound was obtained. It has been shown through the subsequent molecular docking studies and molecular dynamic simulations that Neo6 not only assumes more favorable conformation at the binding pocket of HA but also has stronger binding interaction with its receptor. Accordingly, Neo6 may become a promising candidate for developing new and more powerful drugs for treating influenza. Or at the very least, the findings reported here may provide useful insights to stimulate new strategy in this area

Localized-Statistical Quantification of Human Serum Proteome Associated with Type 2 Diabetes

BACKGROUND: Recent advances in proteomics have shed light to discover serum proteins or peptides as biomarkers for tracking the progression of diabetes as well as understanding molecular mechanisms of the disease. RESULTS: In this work, human serum of non-diabetic and diabetic cohorts was analyzed by proteomic approach. To analyze total 1377 high-confident serum-proteins, we developed a computing strategy called localized statistics of protein abundance distribution (LSPAD) to calculate a significant bias of a particular protein-abundance between these two cohorts. As a result, 68 proteins were found significantly over-represented in the diabetic serum (p<0.01). In addition, a pathway-associated analysis was developed to obtain the overall pathway bias associated with type 2 diabetes, from which the significant over-representation of complement system associated with type 2 diabetes was uncovered. Moreover, an up-stream activator of complement pathway, ficolin-3, was observed over-represented in the serum of type 2 diabetic patients, which was further validated with statistic significance (p = 0.012) with more clinical samples. CONCLUSIONS: The developed LSPAD approach is well fit for analyzing proteomic data derived from biological complex systems such as plasma proteome. With LSPAD, we disclosed the comprehensive distribution of the proteins associated with diabetes in different abundance levels and the involvement of ficolin-related complement activation in diabetes

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data