Estimation of synthetic accessibility score of drug-like molecules based on molecular complexity and fragment contributions

<p>Abstract</p> <p>Background</p> <p>A method to estimate ease of synthesis (synthetic accessibility) of drug-like molecules is needed in many areas of the drug discovery process. The development and validation of such a method that is able to characterize molecule synthetic accessibility as a score between 1 (easy to make) and 10 (very difficult to make) is described in this article.</p> <p>Results</p> <p>The method for estimation of the synthetic accessibility score (SAscore) described here is based on a combination of fragment contributions and a complexity penalty. Fragment contributions have been calculated based on the analysis of one million representative molecules from PubChem and therefore one can say that they capture historical synthetic knowledge stored in this database. The molecular complexity score takes into account the presence of non-standard structural features, such as large rings, non-standard ring fusions, stereocomplexity and molecule size. The method has been validated by comparing calculated SAscores with ease of synthesis as estimated by experienced medicinal chemists for a set of 40 molecules. The agreement between calculated and manually estimated synthetic accessibility is very good with <it>r</it>²= 0.89.</p> <p>Conclusion</p> <p>A novel method to estimate synthetic accessibility of molecules has been developed. This method uses historical synthetic knowledge obtained by analyzing information from millions of already synthesized chemicals and considers also molecule complexity. The method is sufficiently fast and provides results consistent with estimation of ease of synthesis by experienced medicinal chemists. The calculated SAscore may be used to support various drug discovery processes where a large number of molecules needs to be ranked based on their synthetic accessibility, for example when purchasing samples for screening, selecting hits from high-throughput screening for follow-up, or ranking molecules generated by various <it>de novo </it>design approaches.</p

Supersymmetric black holes in 2D dilaton supergravity: baldness and extremality

We present a systematic discussion of supersymmetric solutions of 2D dilaton supergravity. In particular those solutions which retain at least half of the supersymmetries are ground states with respect to the bosonic Casimir function (essentially the ADM mass). Nevertheless, by tuning the prepotential appropriately, black hole solutions may emerge with an arbitrary number of Killing horizons. The absence of dilatino and gravitino hair is proven. Moreover, the impossibility of supersymmetric dS ground states and of nonextremal black holes is confirmed, even in the presence of a dilaton. In these derivations the knowledge of the general analytic solution of 2D dilaton supergravity plays an important role. The latter result is addressed in the more general context of gPSMs which have no supergravity interpretation. Finally it is demonstrated that the inclusion of non-minimally coupled matter, a step which is already nontrivial by itself, does not change these features in an essential way.Comment: 30 pages, LaTeX, v2: mayor revision (rearranged title, shortened abstract, revised introduction, inserted section from appendix to main text, added subsection with new material on non-SUGRA gPSMs, added clarifying remarks at some places, updated references); v3: corrected minor misprints, added note with a new referenc

Differences in intestinal size, structure, and function contributing to feed efficiency in broiler chickens reared at geographically distant locations

The contribution of the intestinal tract to differences in residual feed intake (RFI) has been inconclusively studied in chickens so far. It is also not clear if RFI-related differences in intestinal function are similar in chickens raised in different environments. The objective was to investigate differences in nutrient retention, visceral organ size, intestinal morphology, jejunal permeability and expression of genes related to barrier function, and innate immune response in chickens of diverging RFI raised at 2 locations (L1: Austria; L2: UK). The experimental protocol was similar, and the same dietary formulation was fed at the 2 locations. Individual BW and feed intake (FI) of chickens (Cobb 500FF) were recorded from d 7 of life. At 5 wk of life, chickens (L1, n = 157; L2 = 192) were ranked according to their RFI, and low, medium, and high RFI chickens were selected (n = 9/RFI group, sex, and location). RFI values were similar between locations within the same RFI group and increased by 446 and 464 g from low to high RFI in females and males, respectively. Location, but not RFI rank, affected growth, nutrient retention, size of the intestine, and jejunal disaccharidase activity. Chickens from L2 had lower total body weight gain and mucosal enzyme activity but higher nutrient retention and longer intestines than chickens at L1. Parameters determined only at L1 showed increased crypt depth in the duodenum and jejunum and enhanced paracellular permeability in low vs. high RFI females. Jejunal expression of IL1B was lower in low vs. high RFI females at L2, whereas that of TLR4 at L1 and MCT1 at both locations was higher in low vs. high RFI males. Correlation analysis between intestinal parameters and feed efficiency metrics indicated that feed conversion ratio was more correlated to intestinal size and function than was RFI. In conclusion, the rearing environment greatly affected intestinal size and function, thereby contributing to the variation in chicken RFI observed across locations

Diffusion on a solid surface: Anomalous is normal

We present a numerical study of classical particles diffusing on a solid surface. The particles' motion is modeled by an underdamped Langevin equation with ordinary thermal noise. The particle-surface interaction is described by a periodic or a random two dimensional potential. The model leads to a rich variety of different transport regimes, some of which correspond to anomalous diffusion such as has recently been observed in experiments and Monte Carlo simulations. We show that this anomalous behavior is controlled by the friction coefficient, and stress that it emerges naturally in a system described by ordinary canonical Maxwell-Boltzmann statistics

PubChemSR: A search and retrieval tool for PubChem

<p>Abstract</p> <p>Background</p> <p>Recent years have seen an explosion in the amount of publicly available chemical and related biological information. A significant step has been the emergence of PubChem, which contains property information for millions of chemical structures, and acts as a repository of compounds and bioassay screening data for the NIH Roadmap. There is a strong need for tools designed for scientists that permit easy download and use of these data. We present one such tool, PubChemSR.</p> <p>Implementation</p> <p>PubChemSR (Search and Retrieve) is a freely available desktop application written for Windows using Microsoft <it>.NET </it>that is designed to assist scientists in search, retrieval and organization of chemical and biological data from the PubChem database. It employs SOAP web services made available by NCBI for extraction of information from PubChem.</p> <p>Results and Discussion</p> <p>The program supports a wide range of searching techniques, including queries based on assay or compound keywords and chemical substructures. Results can be examined individually or downloaded and exported in batch for use in other programs such as Microsoft Excel. We believe that PubChemSR makes it straightforward for researchers to utilize the chemical, biological and screening data available in PubChem. We present several examples of how it can be used.</p

MyChemise: A 2D drawing program that uses morphing for visualisation purposes

MyChemise (My Chemical Structure Editor) is a new 2D structure editor. It is designed as a Java applet that enables the direct creation of structures in the Internet using a web browser. MyChemise saves files in a digital format (.cse) and the import and export of .mol files using the appropriate connection tables is also possible

MicroRNA-24 regulates vascularity after myocardial infarction

BACKGROUND: Myocardial infarction leads to cardiac remodeling and development of heart failure. Insufficient myocardial capillary density after myocardial infarction has been identified as a critical event in this process, although the underlying mechanisms of cardiac angiogenesis are mechanistically not well understood. METHODS AND RESULTS: Here, we show that the small noncoding RNA microRNA-24 (miR-24) is enriched in cardiac endothelial cells and considerably upregulated after cardiac ischemia. MiR-24 induces endothelial cell apoptosis, abolishes endothelial capillary network formation on Matrigel, and inhibits cell sprouting from endothelial spheroids. These effects are mediated through targeting of the endothelium-enriched transcription factor GATA2 and the p21-activated kinase PAK4, which were identified by bioinformatic predictions and validated by luciferase gene reporter assays. Respective downstream signaling cascades involving phosphorylated BAD (Bcl-XL/Bcl-2-associated death promoter) and Sirtuin1 were identified by transcriptome, protein arrays, and chromatin immunoprecipitation analyses. Overexpression of miR-24 or silencing of its targets significantly impaired angiogenesis in zebrafish embryos. Blocking of endothelial miR-24 limited myocardial infarct size of mice via prevention of endothelial apoptosis and enhancement of vascularity, which led to preserved cardiac function and survival. CONCLUSIONS: Our findings indicate that miR-24 acts as a critical regulator of endothelial cell apoptosis and angiogenesis and is suitable for therapeutic intervention in the setting of ischemic heart disease. [KEYWORDS: Animals, Apoptosis/drug effects, Arterioles/pathology, Capillaries/pathology, Cell Hypoxia, Cells, Cultured/drug effects/metabolism, Collagen, Drug Combinations, Drug Evaluation, Preclinical, Endothelial Cells/ metabolism/pathology, GATA2 Transcription Factor/biosynthesis/genetics, Gene Expression Profiling, Heart Failure/etiology, Heme Oxygenase-1/biosynthesis/genetics, Laminin, Male, Mice, Mice, Inbred C57BL, MicroRNAs/antagonists & inhibitors/genetics/ physiology, Myocardial Infarc

Graded Poisson-Sigma Models and Dilaton-Deformed 2D Supergravity Algebra

Fermionic extensions of generic 2d gravity theories obtained from the graded Poisson-Sigma model (gPSM) approach show a large degree of ambiguity. In addition, obstructions may reduce the allowed range of fields as given by the bosonic theory, or even prohibit any extension in certain cases. In our present work we relate the finite W-algebras inherent in the gPSM algebra of constraints to algebras which can be interpreted as supergravities in the usual sense (Neuveu-Schwarz or Ramond algebras resp.), deformed by the presence of the dilaton field. With very straightforward and natural assumptions on them --like demanding rigid supersymmetry in a certain flat limit, or linking the anti-commutator of certain fermionic charges to the Hamiltonian constraint-- in the ``genuine'' supergravity obtained in this way the ambiguities disappear, as well as the obstructions referred to above. Thus all especially interesting bosonic models (spherically reduced gravity, the Jackiw-Teitelboim model etc.)\ under these conditions possess a unique fermionic extension and are free from new singularities. The superspace supergravity model of Howe is found as a special case of this supergravity action. For this class of models the relation between bosonic potential and prepotential does not introduce obstructions as well.Comment: 22 pages, LaTeX, JHEP class. v3: Final version, to appear in JHE

Electron-correlation effects in appearance-potential spectra of Ni

Spin-resolved and temperature-dependent appearance-potential spectra of ferromagnetic Nickel are measured and analyzed theoretically. The Lander self-convolution model which relates the line shape to the unoccupied part of the local density of states turns out to be insufficient. Electron correlations and orbitally resolved transition-matrix elements are shown to be essential for a quantitative agreement between experiment and theory.Comment: LaTeX, 6 pages, 2 eps figures included, Phys. Rev. B (in press