Drug discovery projects in the pharmaceutical industry accumulate thousands of chemical structures and ten-thousands of data points from a dozen or more biological and pharmacological assays. A ...sufficient interpretation of the data requires understanding, which molecular families are present, which structural motifs correlate with measured properties, and which tiny structural changes cause large property changes. Data visualization and analysis software with sufficient chemical intelligence to support chemists in this task is rare. In an attempt to contribute to filling the gap, we released our in-house developed chemistry aware data analysis program DataWarrior for free public use. This paper gives an overview of DataWarrior’s functionality and architecture. Exemplarily, a new unsupervised, 2-dimensional scaling algorithm is presented, which employs vector-based or nonvector-based descriptors to visualize the chemical or pharmacophore space of even large data sets. DataWarrior uses this method to interactively explore chemical space, activity landscapes, and activity cliffs.
Emerging evidence suggests that excessive exposure to traffic-derived air pollution during pregnancy may increase the vulnerability to neurodevelopmental alterations that underlie a broad array of ...neuropsychiatric disorders. We present a mouse model for prenatal exposure to urban freeway nanoparticulate matter (nPM). In prior studies, we developed a model for adult rodent exposure to re-aerosolized urban nPM which caused inflammatory brain responses with altered neuronal glutamatergic functions. nPMs are collected continuously for one month from a local freeway and stored as an aqueous suspension, prior to re-aerosolization for exposure of mice under controlled dose and duration. This paradigm was used for a pilot study of prenatal nPM impact on neonatal neurons and adult behaviors. Adult C57BL/6J female mice were exposed to re-aerosolized nPM (350 µg/m(3)) or control filtered ambient air for 10 weeks (3×5 hour exposures per week), encompassing gestation and oocyte maturation prior to mating. Prenatal nPM did not alter litter size, pup weight, or postnatal growth. Neonatal cerebral cortex neurons at 24 hours in vitro showed impaired differentiation, with 50% reduction of stage 3 neurons with long neurites and correspondingly more undifferentiated neurons at Stages 0 and 1. Neuron number after 24 hours of culture was not altered by prenatal nPM exposure. Addition of exogenous nPM (2 µg/ml) to the cultures impaired pyramidal neuron Stage 3 differentiation by 60%. Adult males showed increased depression-like responses in the tail-suspension test, but not anxiety-related behaviors. These pilot data suggest that prenatal exposure to nPM can alter neuronal differentiation with gender-specific behavioral sequelae that may be relevant to human prenatal exposure to urban vehicular aerosols.
In drug discovery, molecules are optimized towards desired properties. In this context, machine learning is used for extrapolation in drug discovery projects. The limits of extrapolation for ...regression models are known. However, a systematic analysis of the effectiveness of extrapolation in drug discovery has not yet been performed. In response, this study examined the capabilities of six machine learning algorithms to extrapolate from 243 datasets. The response values calculated from the molecules in the datasets were molecular weight, cLogP, and the number of sp3-atoms. Three experimental set ups were chosen for response values. Shuffled data were used for interpolation, whereas data for extrapolation were sorted from high to low values, and the reverse. Extrapolation with sorted data resulted in much larger prediction errors than extrapolation with shuffled data. Additionally, this study demonstrated that linear machine learning methods are preferable for extrapolation.
Summary
Mutations in NPRL3, one of three genes that encode proteins of the mTORC1‐regulating GATOR1 complex, have recently been reported to cause cortical dysplasia with focal epilepsy. We have now ...analyzed a multiplex epilepsy family by whole exome sequencing and identified a frameshift mutation (NM_001077350.2; c.1522delG; p.E508Rfs*46) within exon 13 of NPRL3. This truncating mutation causes an epilepsy phenotype characterized by early childhood onset of mainly nocturnal frontal lobe epilepsy. The penetrance in our family was low (three affected out of six mutation carriers), compared to families with either ion channel‐ or DEPDC5‐associated familial nocturnal frontal lobe epilepsy. The absence of apparent structural brain abnormalities suggests that mutations in NPRL3 are not necessarily associated with focal cortical dysplasia but might be able to cause epilepsy by different, yet unknown pathomechanisms.
The Platinum dataset of protein-bound ligand conformations was used to benchmark the ability of the MMFF94s force field to generate bioactive conformations by minimization of randomly generated ...conformers. Torsion angle parameters that generally caused wrong geometries were reparameterized by conducting dihedral scans using ab initio calculations at the MP2 level. This reparameterization resulted in a systematic improvement of generated conformations.
Objective
Alterations of sphingolipid metabolism are implicated in the pathogenesis of many neurodegenerative disorders.
Methods
We identified a homozygous nonsynonymous mutation in CERS1, the gene ...encoding ceramide synthase 1, in 4 siblings affected by a progressive disorder with myoclonic epilepsy and dementia. CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18‐ceramides.
Results
We demonstrated that the mutation decreases C18‐ceramide levels. In addition, we showed that downregulation of CerS1 in a neuroblastoma cell line triggers ER stress response and induces proapoptotic pathways.
Interpretation
This study demonstrates that impairment of ceramide biosynthesis underlies neurodegeneration in humans. Ann Neurol 2014;76:206–212
Emerging evidence emphasizes the strong impact of regulatory genomic elements in neurodevelopmental processes and the complex pathways of brain disorders. The present genome-wide quantitative trait ...loci analyses explore the cis-regulatory effects of single-nucleotide polymorphisms (SNPs) on DNA methylation (meQTL) and gene expression (eQTL) in 110 human hippocampal biopsies. We identify cis-meQTLs at 14,118 CpG methylation sites and cis-eQTLs for 302 3'-mRNA transcripts of 288 genes. Hippocampal cis-meQTL-CpGs are enriched in flanking regions of active promoters, CpG island shores, binding sites of the transcription factor CTCF and brain eQTLs. Cis-acting SNPs of hippocampal meQTLs and eQTLs significantly overlap schizophrenia-associated SNPs. Correlations of CpG methylation and RNA expression are found for 34 genes. Our comprehensive maps of cis-acting hippocampal meQTLs and eQTLs provide a link between disease-associated SNPs and the regulatory genome that will improve the functional interpretation of non-coding genetic variants in the molecular genetic dissection of brain disorders.
Several in-house developed descriptors and our in-house docking tool ActDock were compared with virtual screening on the data set of useful decoys (DUD). The results were compared with the chemical ...fingerprint descriptor from ChemAxon and with the docking results of the original DUD publication. The DUD is the first published data set providing active molecules, decoys, and references for crystal structures of ligand-target complexes. The DUD was designed for the purpose of evaluating docking programs. It contains 2950 active compounds against a total of 40 target proteins. Furthermore, for every ligand the data set contains 36 structurally dissimilar decoy compounds with similar physicochemical properties. We extracted the ligands from the target proteins to extend the applicability of the data set to include ligand based virtual screening. From the 40 target proteins, 37 contained ligands that we used as query molecules for virtual screening evaluation. With this data set a large comparison was done between four different chemical fingerprints, a topological pharmacophore descriptor, the Flexophore descriptor, and ActDock. The Actelion docking tool relies on a MM2 forcefield and a pharmacophore point interaction statistic for scoring; the details are described in this publication. In terms of enrichment rates the chemical fingerprint descriptors performed better than the Flexophore and the docking tool. After removing molecules chemically similar to the query molecules the Flexophore descriptor outperformed the chemical descriptors and the topological pharmacophore descriptors. With the similarity matrix calculations used in this study it was shown that the Flexophore is well suited to find new chemical entities via “scaffold hopping”. The Flexophore descriptor can be explored with a Java applet at http://www.cheminformatics.ch in the submenu Tools→Flexophore. Its usage is free of charge and does not require registration.
Recent studies reported DEPDC5 loss‐of‐function mutations in different focal epilepsy syndromes. Here we identified 1 predicted truncation and 2 missense mutations in 3 children with rolandic ...epilepsy (3 of 207). In addition, we identified 3 families with unclassified focal childhood epilepsies carrying predicted truncating DEPDC5 mutations (3 of 82). The detected variants were all novel, inherited, and present in all tested affected (n = 11) and in 7 unaffected family members, indicating low penetrance. Our findings extend the phenotypic spectrum associated with mutations in DEPDC5 and suggest that rolandic epilepsy, albeit rarely, and other nonlesional childhood epilepsies are among the associated syndromes. Ann Neurol 2014;75:788–792
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