Discovery of Picomolar ABL Kinase Inhibitors Equipotent for Wild Type and T315I Mutant via Structure-Based de Novo Design

Although the constitutively activated break-point cluster region–Abelson (ABL) tyrosine kinase is known to cause chronic myelogenous leukemia (CML), the prevalence of drug-resistant ABL mutants has made it difficult to develop effective anti-CML drugs. With the aim to identify new lead compounds for anti-CML drugs, we carried out a structure-based de novo design using the scoring function improved by implementing an accurate solvation free energy term. This approach led to the identification of ABL inhibitors equipotent for the wild type and the most drug-resistant T315I mutant of ABL at the picomolar level. Decomposition analysis of the binding free energy showed that a decrease in the desolvation cost for binding in the ATP-binding site could be as important as the strengthening of enzyme–inhibitor interaction to enhance the potency of an ABL inhibitor with structural modifications. A similar energetic feature was also observed in free energy perturbation (FEP) calculations. Consistent with the previous experimental and computational studies, the hydrogen bond interactions with the backbone groups of Met318 proved to be the most significant binding forces to stabilize the inhibitors in the ATP-binding sites of the wild type and T315I mutant. The results of molecular dynamics simulations indicated that the dynamic stabilities of the hydrogen bonds between the inhibitors and Met318 should also be considered in designing the potent common inhibitors of the wild-type and T315I mutant of ABL

Application of Fragment-Based de Novo Design to the Discovery of Selective Picomolar Inhibitors of Glycogen Synthase Kinase‑3 Beta

A systematic fragment-based de novo design procedure was developed and applied to discover new potent and selective inhibitors of glycogen synthase kinase-3 beta (GSK3β). Candidate inhibitors were generated to simultaneously maximize the biochemical potency and the specificity for GSK3β through three design steps: identification of the optimal molecular fragments for the three sub-binding regions, design of proper linking moieties to connect the fragmental building blocks, and final scoring of the generated molecules. By virtue of modifying the ligand hydration free energy term in the scoring function using hybrid scaled particle theory and the extended solvent-contact model, we identified several GSK3β inhibitors with biochemical potencies ranging from low nanomolar to picomolar levels. Among them, the two most potent inhibitors (<b>12</b> and <b>27</b>) are anticipated to serve as promising starting points of drug discovery for various diseases caused by GSK3β because of the high specificity for the inhibition of GSK3β

Identification of Novel Inhibitors of Tropomyosin-Related Kinase A through the Structure-Based Virtual Screening with Homology-Modeled Protein Structure

Tropomyosin-related kinase A (TrkA) is a promising target for the development of cancer and pain therapeutics. Here, we report the first successful example of the use of a structure-based virtual screening to identify novel TrkA inhibitors. The accuracy of the virtual screening was improved by introducing an accurate solvation free energy term into the original AutoDock scoring function. We applied a drug design protocol involving homology modeling, docking analysis of a large chemical library, and enzyme inhibition assays to identify six structurally diverse TrkA inhibitors with <i>K</i>_<i>d</i> values ranging from 3 to 40 μM. The significant potencies and good physicochemical properties of these drug candidates strongly support their consideration in a development effort that would involve structure–activity relationship (SAR) studies to optimize the inhibitory activities. We also addressed the structural and energetic features associated with binding of the newly identified inhibitors in the ATP-binding site of TrkA. The results indicate that any structural modifications introduced for the purpose of enhancing the activity of TrkA inhibitors should maximize the attractive interactions within the ATP-binding site and simultaneously minimize the desolvation cost for complexation

Advantages of Mobile Liquid-Crystal Phase of AIE Luminogens for Effective Solid-State Emission

We investigate aggregation-induced emission (AIE) characters of bulk tetraphenylethene (<b>TPE</b>) derivatives with nonpolar and polar exterior chains. The bulk <b>TPE</b> derivatives with nonpolar dodecyl and polar di­(ethylene oxide) chains are in liquid crystal (LC) and crystalline phases, respectively, at room temperature. The mobile LC character of the <b>TPE</b> derivatives in bulk is crucial for high AIE efficiency because the mobile LC character is effective in minimizing the number of undesirable nonemissive local sites in aggregates and inducing a homogeneous zigzag-stacked columnar structure with j-type coupled transition dipoles of the <b>TPE</b> derivatives. The mobile LC characteristics of AIE luminogens can be advantageous for highly efficient solid-state emission

Additional file 1: Figure S1. of Evaluation of anti-tumorigenic activity of BP3B against colon cancer with patient-derived tumor xenograft model

To measure the status of tumor angiogenesis in BP3B-treated tumors, immunostaining of Tie-2 receptor tyrosine kinase was performed with specific antibody (brown). The intensity of Tie-2-positive cell was quantified with ImmunoRatio software. Cell nuclei were stained with hematoxylin (blue). Scale bars are 50 mm. * p < 0.05. (PDF 421 kb

Design, Synthesis, and Evaluation of 3,5-Disubstituted 7-Azaindoles as Trk Inhibitors with Anticancer and Antiangiogenic Activities

Tropomyosin-related kinase A (TrkA) is considered a promising target in the development of a therapeutic treatment of cancer and pain. In this study, we designed and synthesized a series of novel 7-azaindole-based Trk kinase inhibitors through the structure-based design strategy. By varying the functional groups at the 3 and 5 positions of a 7-azaindole scaffold, we studied the structure–activity relationships (SAR) profiles and identified a series of potent Trk inhibitors. Representative derivatives showed desirable activity in cellular proliferation and apoptosis assays. Moreover, these inhibitors exhibited noteworthy antiangiogenic activity

Features of the Blood Expression Axes.

1<p>See <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003362#pgen.1003362.s003" target="_blank">Dataset S3</a> for details of the GO catergories, number of genes, and significance levels.</p>2<p>Simply reflecting enrichment frm the ToppFun analysis, not meant to imply that these are the only regulatory factors or that there is direct evidence for their involvement in regulation of the axes. <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003362#pgen.1003362.s003" target="_blank">Dataset S3</a> shows that each bind only a subset of genes in the axis.</p>3<p>The number of genes associated with each Axis in a multivariate model including all 9 Axes, at Bonferroni significance and in common between the CHDWB and Morocco studies.</p

Common axes explain a large proportion of expression variation.

<p>(A) Hierarchical clustering of the PC1 scores for 24 Expression Modules in Ref <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003362#pgen.1003362-Chaussabel1" target="_blank">[12]</a> in the Atlanta CHDWB and Morocco datasets shows complete agreement in clustering into 6 meta-modules. These define 6 of the Axes described here, while a 7^th Axis emerged on further decomposition of Module 3.1 (B) The frequency distribution of proportion of variance explained by all 9 Axes for each of 14,343 transcript probes (light green) and 7,538 transcript probes (dark green) Bonferroni significant for at least one Axis in a multiple regression. Inclusion of the two additional axes not corresponding to the Chaussabel modules only explains an extra 4% of the variance relative to the first seven. (C) The number of Bonferroni significant axes per transcript in the CHDWB dataset, showing that 39% (5622/14343) of transcript probes associate most strongly with a single axis.</p

Axis analysis of the Snyderome.

<p>19 sequential RNA-Seq profiles were mined for BIT Axis scores, which are plotted relative to sampling day for the individual described in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003362#pgen.1003362-Chen2" target="_blank">[20]</a>. P-values indicate the signifcance associated with t-test comparison of high blood glucose versus normal (Axes 1, 5 and 6) or the comparison of acute phase of viral infection - Days 0, 290 and 292 - versus the remainder. Colors indicate the phases of human rhinovirus infection (HRV; blue), recovery (yellow), respiratory syncitial virus infection (RSV; green), and pre-diabetes/high blood glucose (red). The green triangle corresponds to a spike in cytokine profile at day 301, which does not obviously impact the Axes. The RSV had not yet cleared at days 307 and 311 when the pre-diabetic state first became apparent, so these points are shown in green and red. The other Axes did not show significant changes.</p

Monthly variations in aneurysmal subarachnoid hemorrhage incidence and mortality: Correlation with weather and pollution

<div><p>Background and purpose</p><p>Although the effect of weather and air pollution on the occurrence of subarachnoid hemorrhage (SAH) has been investigated, results have remained inconsistent. The present study aimed to determine the seasonality of aneurysmal subarachnoid hemorrhage occurrence and mortality.</p><p>Methods</p><p>We used the National Inpatient Sample database to evaluate the effect of meteorological factors and air pollutants on patients with subarachnoid hemorrhage in Korea between 2011 and 2014. Monthly variations in SAH occurrence and mortality were analyzed using locally weighted scatter plot smoothing curves. Multivariate Poisson generalized linear regression models were used to evaluate potential independent meteorological and pollutant variables associated with SAH occurrence and mortality.</p><p>Results</p><p>In total, 21,407 patients who underwent clip or coil treatment owing to aneurysmal SAH in Korea from January 1, 2011, to December 31, 2014, were included. The crude incidence rate of SAH in Korea was 10.5 per 100,000 people per year. An approximately 0.5% lower risk of SAH was observed per 1°C increase in mean monthly temperature (relative risk, 0.995; 95% confidence interval [CI], 0.992–0.997; p < 0.001), while an approximately 2.3% higher risk of SAH was observed per 1°C increase in mean monthly diurnal temperature.</p><p>Conclusions</p><p>We showed distinct patterns of seasonal and monthly variation in the occurrence and mortality of SAH. Our findings suggest that meteorological factors may play an important role in monthly variations in the occurrence of aneurysmal SAH.</p></div