AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-76543 Modeling of Molecular Interaction between Apoptin, BCR-Abl and CrkL- An Alternative Approach to Conventional Rational Drug Design

In this study we have calculated a 3D structure of apoptin and through modeling and docking approaches, we show its interaction with Bcr-Abl oncoprotein and its downstream signaling components, following which we confirm some of the newly-found interactions by biochemical methods. Bcr-Abl oncoprotein is aberrantly expressed in chronic myelogenous leukaemia (CML). It has several distinct functional domains in addition to the Abl kinase domain. The SH3 and SH2 domains cooperatively play important roles in autoinhibiting its kinase activity. Adapter molecules such as Grb2 and CrkL interact with proline-rich region and activate multiple Bcr-Abl downstream signaling pathways that contribute to growth an

Solution Structure of C. elegans UNC-6: A Nematode Paralogue of the Axon Guidance Protein Netrin-1

UNCoordinated-6 (UNC-6) was the first member of the netrin family to be discovered in Caenorhabditis elegans. With homology to human netrin-1, it is a key signaling molecule involved in directing axon migration in nematodes. Similar to netrin-1, UNC-6 interacts with multiple receptors (UNC-5 and UNC-40, specifically) to guide axon migration in development. As a result of the distinct evolutionary path of UNC-6 compared to vertebrate netrins, we decided to employ an integrated approach to study its solution behavior and compare it to the high-resolution structure we previously published on vertebrate netrins. Dynamic light scattering and analytical ultracentrifugation on UNC-6 (with and without its C-domain) solubilized in a low-ionic strength buffer suggested that UNC-6 forms high-order oligomers. An increase in the buffer ionic strength resulted in a more homogeneous preparation of UNC-6, that was used for subsequent solution x-ray scattering experiments. Our biophysical analysis of UNC-6 Delta C solubilized in a high-ionic strength buffer suggested that it maintains a similar head-to-stalk arrangement as netrins -1 and -4. This phenomenon is thought to play a role in the signaling behavior of UNC-6 and its ability to move throughout the extracellular matrix

Apoptin, a tumor-selective killer

Apoptin, a small protein from chicken anemia virus, has attracted great attention, because it specifically kills tumor cells while leaving normal cells unharmed. The subcellular localization of apoptin appears to be crucial for this tumor-selective activity. In normal cells, apoptin resides in the cytoplasm, whereas in cancerous cells it translocates into the nucleus. The nuclear translocation of apoptin is largely controlled by its phosphorylation. In tumor cells, apoptin causes the nuclear accumulation of survival kinases including Akt and is phosphorylated by CDK2. Thereby, apoptin redirects survival signals into cell death responses. Apoptin also binds as a multimeric complex to DNA and interacts with several nuclear targets, such as the anaphase-promoting complex, resulting in a G2/M phase arrest. The proapoptotic signal of apoptin is then transduced from the nucleus to cytoplasm by Nur77, which triggers a p53-independent mitochondrial death pathway. In this review, we summarize recent discoveries of apoptin's mechanism of action that might provide intriguing insights for the development of novel tumor-selective anticancer drugs.Invited Review</p

Sister Experience Trophic Ulcers in Patient Care

Bakalaura darba tēma „Māsu pieredze trofisko čūlu pacientu aprūpē”. Darba izstrādei tika izvirzīts mērķis – noskaidrot māsu pieredzi, trofisko čūlu pacientu aprūpē. Pētījums ir balstīts uz aptaujas rezultātiem un zinātniski teorētiskās literatūras analīzi. Pētniecības teorētiskajā daļā tiek aprakstīta trofisko čūlu klasifikācija, klīniskā aina, raksturīgākās īpašības, komplikācijas, ārstēšana un profilakses pasākumi. Pētniecības darbā izmantota K. Rojas māszinību teorija, kas ir orientēta uz cilvēka mijiedarbību ar mainīgo apkārtējo vidi, kas stimulē adaptācijas reakciju veidošanos. Pētniecības darba praktiskajā daļā iekļauts aptaujas anketu apkopojums, rezultātu analīze, secinājumi un priekšlikumi. Tika analizēti un apkopoti 28 literatūras avoti. Pētījumā tika izmantota kvantitatīvā pētniecības metode – anketēšana, kas sastāvēja no 13 jautājumiem. Praktiskajā daļā uzrādīti pētījuma rezultāti, kas attēloti diagrammās, ir veikta šo rezultātu analīze un izdarīti secinājumi. Analizējot pētījumu var secināt, ka medicīnas māsai ir ļoti daudz darba sakarā ar tiem pacientiem, kuriem ļoti sīki ir jāpaskaidro trofisko čūlu aprūpi, gan stacionārā, gan mājās. Medicīnas māsas zināšanas ir minimālas ja tā strādā nodaļā, kura ar trofisko čūlu pacientiem saskare ir ierobežota. Tomēr, tai ir ļoti liela loma aprūpes izskaidrošanai, palīdzības sniegšanai, un atbalstīšanai. Māsu pieredze trofisko čūlu pacientu aprūpē ir pietiekoša, jo ņemot kopumā to, ka māsām vēl ir daudz visdažādāka darba, viņas ar to aprūpi tiek gala. Pētījuma dati apstiprina izvirzīto hipotēzi.The theme of the „Sister experience trophic ulcers in patient care”. The development was the aim – to clarify her experience trophic ulcers in patient care. The study is based on the results of the survey and the theoretical literature and analysis. The theoretical part of the research is described in the trophic ulcers classification, clinical picture characteristic properties, complications, treatments and preventive measures. Research work used K. Rojas nursing theory that is focused on the human interaction with the environment that stimulates the formation of adaptation responses. Research work included in the summary, the analysis of the results of the questionnaire, the conclusions and proposals. Was analysed and collected 28 literary sources. The study used a quantitative research method – surveys, which consisted of 13 questions. In the practice session at the presentation of the results of the study, which displayed charts is performed analysis of those results and conclusions. The analysis of the study may be concluded as a nurse is a lot of work in connection with those which need to be clarified very detailed trophic ulcers care, both in hospital and at home. The nurse's knowledge is minimal if it is working with the department, which trophic ulcers in patients contact is limited. However, it has a very large role in the health-care world, assistance and support. Her experience is sufficient trophic ulcers in patient care since, in general, the sisters still has a lot of work they take with their care is final. The study data support the hypothesis