Spherical harmonics coeffcients for ligand-based virtual screening of cyclooxygenase inhibitors

Background: Molecular descriptors are essential for many applications in computational chemistry, such as ligand-based similarity searching. Spherical harmonics have previously been suggested as comprehensive descriptors of molecular structure and properties. We investigate a spherical harmonics descriptor for shape-based virtual screening. Methodology/Principal Findings: We introduce and validate a partially rotation-invariant three-dimensional molecular shape descriptor based on the norm of spherical harmonics expansion coefficients. Using this molecular representation, we parameterize molecular surfaces, i.e., isosurfaces of spatial molecular property distributions. We validate the shape descriptor in a comprehensive retrospective virtual screening experiment. In a prospective study, we virtually screen a large compound library for cyclooxygenase inhibitors, using a self-organizing map as a pre-filter and the shape descriptor for candidate prioritization. Conclusions/Significance: 12 compounds were tested in vitro for direct enzyme inhibition and in a whole blood assay. Active compounds containing a triazole scaffold were identified as direct cyclooxygenase-1 inhibitors. This outcome corroborates the usefulness of spherical harmonics for representation of molecular shape in virtual screening of large compound collections. The combination of pharmacophore and shape-based filtering of screening candidates proved to be a straightforward approach to finding novel bioactive chemotypes with minimal experimental effort

Spherical Harmonics Coefficients for Ligand-Based Virtual Screening of Cyclooxygenase Inhibitors

Molecular descriptors are essential for many applications in computational chemistry, such as ligand-based similarity searching. Spherical harmonics have previously been suggested as comprehensive descriptors of molecular structure and properties. We investigate a spherical harmonics descriptor for shape-based virtual screening.We introduce and validate a partially rotation-invariant three-dimensional molecular shape descriptor based on the norm of spherical harmonics expansion coefficients. Using this molecular representation, we parameterize molecular surfaces, i.e., isosurfaces of spatial molecular property distributions. We validate the shape descriptor in a comprehensive retrospective virtual screening experiment. In a prospective study, we virtually screen a large compound library for cyclooxygenase inhibitors, using a self-organizing map as a pre-filter and the shape descriptor for candidate prioritization.12 compounds were tested in vitro for direct enzyme inhibition and in a whole blood assay. Active compounds containing a triazole scaffold were identified as direct cyclooxygenase-1 inhibitors. This outcome corroborates the usefulness of spherical harmonics for representation of molecular shape in virtual screening of large compound collections. The combination of pharmacophore and shape-based filtering of screening candidates proved to be a straightforward approach to finding novel bioactive chemotypes with minimal experimental effort

Gegenüberstellung der Simulationsfunktionalitäten von Werkzeugen zur Geschäftsprozessmodellierung

Geschäftsprozesse beschreiben, über die Darstellung von Aktivitäten respektive Vorgängen, die Abläufe der Leistungserstellung in einer Unternehmung. Ziel bei der Planung ist es, die Prozesse so effizient und effektiv wie möglich zu gestalten, um mit möglichst wenig eingesetzten Ressourcen ein vordefiniertes Ziel zu erreichen. Effizienz und Effektivität der Prozesse sind dabei entscheidende Faktoren für die Wettbewerbsposition einer Unternehmung, da die realen Kosten der Leistungserstellung aus den Abläufen, die wiederum Ressourcen beanspruchen, resultieren. Um Geschäftsprozesse zu optimieren, können mathematisch - analytische Verfahren angewandt werden. Diese mathematischen Verfahren erlauben es, Geschäftsprozesse und -ketten als geschlossene Ausdrücke zu formulieren und optimal zu lösen. Die analytischen Verfahren scheitern allerdings, sobald die Geschäftsprozesse eine gewisse Komplexität aufweisen. Gemeint sind hochflexible Geschäftsprozesse, die sich dadurch auszeichnen, dass sie entweder nicht vollständig planbar sind, da prozessrelevante Bezugsgrößen unbekannt oder variabel sind, oder diese nicht losgelöst vom Anwendungskontext betrachtet werden können. Zusätzlich komplexitätssteigernd wirkt sich eine zeitliche Überlappung zwischen Planung und Ausführung des Prozesses aus. Um diese komplexen Geschäftsprozesse nachvollziehen und untersuchen zu können und somit einen Ansatz für die Optimierung zu schaffen, bietet sich hier eine Simulation dieser Prozesse an. Ein Simulationsmodell besteht aus einer möglichst realitätsnahen Nachbildung eines Ablaufs in einem Modell und dient der Entscheidungsunterstützung

Mouse Liver Compensates Loss of Sgpl1 by Secretion of Sphingolipids into Blood and Bile

Sphingosine 1 phosphate (S1P) lyase (Sgpl1) catalyses the irreversible cleavage of S1P and thereby the last step of sphingolipid degradation. Loss of Sgpl1 in humans and mice leads to accumulation of sphingolipids and multiple organ injuries. Here, we addressed the role of hepatocyte Sgpl1 for regulation of sphingolipid homoeostasis by generating mice with hepatocyte-specific deletion of Sgpl1 (Sgpl1HepKO mice). Sgpl1HepKO mice had normal body weight, liver weight, liver structure and liver enzymes both at the age of 8 weeks and 8 months. S1P, sphingosine and ceramides, but not glucosylceramides or sphingomyelin, were elevated by ~1.5–2-fold in liver, and this phenotype did not progress with age. Several ceramides were elevated in plasma, while plasma S1P was normal. Interestingly, S1P and glucosylceramides, but not ceramides, were elevated in bile of Sgpl1HepKO mice. Furthermore, liver cholesterol was elevated, while LDL cholesterol decreased in 8-month-old mice. In agreement, the LDL receptor was upregulated, suggesting enhanced uptake of LDL cholesterol. Expression of peroxisome proliferator-activated receptor-γ, liver X receptor and fatty acid synthase was unaltered. These data show that mouse hepatocytes largely compensate the loss of Sgpl1 by secretion of accumulating sphingolipids in a specific manner into blood and bile, so that they can be excreted or degraded elsewher

Causes of genome instability: the effect of low dose chemical exposures in modern society.

Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis

Editorial for Special Issue “Lipid as a Cancer Therapeutic Target”

Lipids are structural components of membranes [...

Sphingolipids in Inflammation

The etiology of many diseases results from the dysregulation of inflammation. Understanding the molecular mechanisms controlling the inflammatory response is essential to formulate therapeutic strategies for the treatment of inflammatory conditions. In fact, substantial research has unveiled important aspects of the inflammatory machinery, both at the cellular and molecular levels. Recently, sphingolipids (Sph) have emerged as signaling molecules that regulate many cell functions, and ample evidence emphasizes their role in the regulation of inflammatory responses. ..

The Many Facets of Sphingolipids in the Specific Phases of Acute Inflammatory Response

This review provides an overview on components of the sphingolipid superfamily, on their localization and metabolism. Information about the sphingolipid biological activity in cell physiopathology is given. Recent studies highlight the role of sphingolipids in inflammatory process. We summarize the emerging data that support the different roles of the sphingolipid members in specific phases of inflammation: (1) migration of immune cells, (2) recognition of exogenous agents, and (3) activation/differentiation of immune cells