Polypharmacological <i>in Silico</i> Bioactivity Profiling and Experimental Validation Uncovers Sedative-Hypnotic Effects of Approved and Experimental Drugs in Rat

In this work, we describe the computational (“<i>in silico</i>”) mode-of-action analysis of CNS-active drugs, which is taking both <i>multiple simultaneous hypotheses</i> as well as <i>sets of protein targets</i> for each mode-of-action into account, and which was followed by successful prospective <i>in vitro</i> and <i>in vivo</i> validation. Using sleep-related phenotypic readouts describing both efficacy and side effects for 491 compounds tested in rat, we defined an “optimal” (desirable) sleeping pattern. Compounds were subjected to <i>in silico</i> target prediction (which was experimentally confirmed for 21 out of 28 cases), followed by the utilization of decision trees for deriving polypharmacological bioactivity profiles. We demonstrated that predicted bioactivities improved classification performance compared to using only structural information. Moreover, DrugBank molecules were processed <i>via</i> the same pipeline, and compounds in many cases not annotated as sedative-hypnotic (alcaftadine, benzatropine, palonosetron, ecopipam, cyproheptadine, sertindole, and clopenthixol) were prospectively validated <i>in vivo</i>. Alcaftadine, ecopipam cyproheptadine, and clopenthixol were found to promote sleep as predicted, benzatropine showed only a small increase in NREM sleep, whereas sertindole promoted wakefulness. To our knowledge, the sedative-hypnotic effects of alcaftadine and ecopipam have not been previously discussed in the literature. The method described extends previous single-target, single-mode-of-action models and is applicable across disease areas

Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery

Impressive progress in genome sequencing, protein expression and high-throughput crystallography and NMR has radically transformed the opportunities to use protein three-dimensional structures to accelerate drug discovery, but the quantity and complexity of the data have ensured a central place for informatics. Structural biology and bioinformatics have assisted in lead optimization and target identification where they have well established roles; they can now contribute to lead discovery, exploiting high-throughput methods of structure determination that provide powerful approaches to screening of fragment binding

Fast and accurate HLA typing from short-read next-generation sequence data with xHLA

The HLA gene complex on human chromosome 6 is one of the most polymorphic regions in the human genome and contributes in large part to the diversity of the immune system. Accurate typing of HLA genes with short-read sequencing data has historically been difficult due to the sequence similarity between the polymorphic alleles. Here, we introduce an algorithm, xHLA, that iteratively refines the mapping results at the amino acid level to achieve 99-100% four-digit typing accuracy for both class I and II HLA genes, taking only [Formula: see text]3 min to process a 30× whole-genome BAM file on a desktop computer

Molecular mechanism of α-synuclein aggregation on lipid membranes revealed.

Acknowledgements: We thank Patrick Connelly for discussions about the thermodynamics and kinetics of aggregate formation and Celine Galvagnion and Alexander Buell for their insightful feedback and their help in refining the presentation of our results. We would like to acknowledge funding from the European Research Council through the ERC grant DiProPhys (agreement ID 101001615) and the Swedish Research Council, grant number VR 2015-00143.The central hallmark of Parkinson's disease pathology is the aggregation of the α-synuclein protein, which, in its healthy form, is associated with lipid membranes. Purified monomeric α-synuclein is relatively stable in vitro, but its aggregation can be triggered by the presence of lipid vesicles. Despite this central importance of lipids in the context of α-synuclein aggregation, their detailed mechanistic role in this process has not been established to date. Here, we use chemical kinetics to develop a mechanistic model that is able to globally describe the aggregation behaviour of α-synuclein in the presence of DMPS lipid vesicles, across a range of lipid and protein concentrations. Through the application of our kinetic model to experimental data, we find that the reaction is a co-aggregation process involving both protein and lipids and that lipids promote aggregation as much by enabling fibril elongation as by enabling their initial formation. Moreover, we find that the primary nucleation of lipid-protein co-aggregates takes place not on the surface of lipid vesicles in bulk solution but at the air-water and/or plate interfaces, where lipids and proteins are likely adsorbed. Our model forms the basis for mechanistic insights, also in other lipid-protein co-aggregation systems, which will be crucial in the rational design of drugs that inhibit aggregate formation and act at the key points in the α-synuclein aggregation cascade

Fast and accurate HLA typing from short-read next-generation sequence data with xHLA

The HLA gene complex on human chromosome 6 is one of the most polymorphic regions in the human genome and contributes in large part to the diversity of the immune system. Accurate typing of HLA genes with short-read sequencing data has historically been difficult due to the sequence similarity between the polymorphic alleles. Here, we introduce an algorithm, xHLA, that iteratively refines the mapping results at the amino acid level to achieve 99-100% four-digit typing accuracy for both class I and II HLA genes, taking only [Formula: see text]3 min to process a 30× whole-genome BAM file on a desktop computer

Why do adolescents with bulimia nervosa choose not to involve their parents in treatment?

Original article can be found at http://www.springerlink.com Copyright Springer [Full text of this article is not available in the UHRA]Background: Although the use of family therapy for adolescents with anorexia nervosa is well established, there has been limited research into the efficacy of family therapy in adolescents with bulimia nervosa (BN). No previous research has investigated why individuals with BN do or do not involve their parents in treatment. This is an exploratory study aimed at determining whether there are any differences between these individuals in terms of eating disorder symptomatology, psychopathology, familial risk factors, patients’ perception of parental expressed emotion (EE) and family functioning. Methods: Participants were 85 adolescents with BN or Eating Disorder Not Otherwise Specified, recruited to a randomised controlled evaluation of the cost-effectiveness of cognitive-behavioural guided self-care vs. family therapy. Participants were interviewed regarding the history of their eating disorder and completed self-report measures. Results: Patients who did not involve their parents in treatment were significantly older, had more chronic eating disorder symptoms, exhibited more co-morbid and impulsive behaviours and rated their mothers higher in EE. However, they did not have more severe eating disorder symptomatology. Conclusions: These preliminary findings, although in need of replication with a larger sample and limited by the attrition rate in some of the self-report measures, indicate that patients who did not involve their parents in treatment may perceive their mothers as having a more blaming and negative attitude towards the patient’s illness. Public awareness about BN needs to be raised, focusing on reducing the stigma and negative views attached to this illness.Peer reviewe