Virtual-screening workflow tutorials and prospective results from the Teach-Discover-Treat competition 2014 against malaria.
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ABSTRACT:
SUBMITTER: Riniker S
PROVIDER: S-EPMC5580409 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The 2012 Teach-Discover-Treat (TDT) community-wide experiment provided a unique opportunity to test prospective virtual screening protocols targeting the anti-malarial target dihydroorotate dehydrogenase (DHODH). Facilitated by ZincPharmer, an open access online interactive pharmacophore search of the ZINC database, the experience resulted in the development of a novel classification scheme that successfully predicted the bound structure of a non-triazolopyrimidine inhibitor, as well as an overall hit rate of 27% of tested active compounds from multiple novel chemical scaffolds. The general approach entailed exhaustively building and screening sparse pharmacophore models comprising of a minimum of three features for each bound ligand in all available DHODH co-crystals and iteratively adding features that increased the number of known binders returned by the query. Collectively, the TDT experiment provided a unique opportunity to teach computational methods of drug discovery, develop innovative methodologies and prospectively discover new compounds active against DHODH.
| S-EPMC4530941 | biostudies-literature
Project description:Explicit emphasis on teaching science process skills leads to both gains in the skills themselves and, strikingly, deeper understanding of content. Here, we created and tested a series of online, interactive tutorials with the goal of helping undergraduate students develop science process skills. We designed the tutorials in accordance with evidence-based multimedia design principles and student feedback from usability testing. We then tested the efficacy of the tutorials in an introductory undergraduate biology class. On the basis of a multivariate ordinary least-squares regression model, students who received the tutorials are predicted to score 0.82 points higher on a 15-point science process skill assessment than their peers who received traditional textbook instruction on the same topic. This moderate but significant impact indicates that well-designed online tutorials can be more effective than traditional ways of teaching science process skills to undergraduate students. We also found trends that suggest the tutorials are especially effective for nonnative English-speaking students. However, due to a limited sample size, we were unable to confirm that these trends occurred due to more than just variation in the student group sampled.
| S-EPMC5998323 | biostudies-literature
Project description:Background:Spinal cord stimulation (SCS) is a proven and effective treatment for neuropathic pain conditions such as failed back surgery syndrome (FBSS). The hypothesis that different settings for SCS parameters activate unique, pain-relieving mechanisms has boosted the development of various SCS paradigms. High density spinal cord stimulation (HD-SCS) is one of those promising, novel stimulation forms characterized by subthreshold stimulation, delivering more pulses per second and a higher pulse density to the spinal cord than conventional SCS. Objectives:The aim of DISCOVER is to gather evidence about the effectiveness, feasibility, and (possible) side effects of HD stimulation. Methods:The prospective, non-interventional, multi-center, clinical study, DISCOVER, is currently restricted to Belgium where 19 neuromodulation centers were selected. Patient recruitment started in October 2016 and is expected to end in October 2017. Subjects included are (1) patients with insufficient pain relief from conventional SCS or (2) neurostimulation-naïve patients suited for SCS. Patients will be assessed 1 month, 3 months, and 12 months after conversion to HD-SCS settings. Each patient's visit will include: a numerical rating scale (NRS), Oswestry disability index (ODI), Pittsburgh sleep quality index (PSQI), EQ-5D, a pain map, registration of SCS settings, and a list of used pain medication. Conclusions:Although promising results have been reported, adequate registration of its effectiveness and (possible) side-effects remains an unmet need. Main results are expected in 2019.
| S-EPMC5800302 | biostudies-literature
Project description:Discovering modes of action and predictive biomarkers of drug-induced structural cardiotoxicity offers the potential to improve cardiac safety assessment of lead compounds and enhance preclinical to clinical translation during drug development. Cardiac microtissues are a promising, physiologically relevant, in vitro model, each composed of ca. 500 cells. While untargeted metabolomics is capable of generating hypotheses on toxicological modes of action and discovering metabolic biomarkers, applying this technology to low-biomass microtissues in suspension is experimentally challenging. Thus, we first evaluated a filtration-based approach for harvesting microtissues and assessed the sensitivity and reproducibility of nanoelectrospray direct infusion mass spectrometry (nESI-DIMS) measurements of intracellular extracts, revealing samples consisting of 28 pooled microtissues, harvested by filtration, are suitable for profiling the intracellular metabolome and lipidome. Subsequently, an extensive workflow combining nESI-DIMS untargeted metabolomics and lipidomics of intracellular extracts with ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) analysis of spent culture medium, to profile the metabolic footprint and quantify drug exposure concentrations, was implemented. Using the synthetic drug and model cardiotoxin sunitinib, time-resolved metabolic and lipid perturbations in cardiac microtissues were investigated, providing valuable data for generating hypotheses on toxicological modes of action and identifying putative biomarkers such as disruption of purine metabolism and perturbation of polyunsaturated fatty acid levels.
| S-EPMC8470535 | biostudies-literature
Project description:Objective. To determine whether using 3-dimensional (3D) technology to teach pharmacy students about the molecular basis of the interactions between drugs and their targets is more effective than traditional lecture using 2-dimensional (2D) graphics.Design. Second-year students enrolled in a 4-year masters of pharmacy program in the United Kingdom were randomly assigned to attend either a 3D or 2D presentation on 3 drug targets, the ?-adrenoceptor, the Na(+)-K(+) ATPase, and the nicotinic acetylcholine receptor.Assessment. A test was administered to assess the ability of both groups of students to solve problems that required analysis of molecular interactions in 3D space. The group that participated in the 3D teaching presentation performed significantly better on the test than the group who attended the traditional lecture with 2D graphics. A questionnaire was also administered to solicit students' perceptions about the 3D experience. The majority of students enjoyed the 3D session and agreed that the experience increased their enthusiasm for the course.Conclusions. Viewing a 3D presentation of drug-receptor interactions improved student learning compared to learning from a traditional lecture and 2D graphics.
| S-EPMC3578324 | biostudies-literature
Project description:The use of virtual screening has become increasingly central to the drug development pipeline, with ligand-based virtual screening used to screen databases of compounds to predict their bioactivity against a target. These databases can only represent a small fraction of chemical space, and this paper describes a method of exploring synthetic space by applying virtual reactions to promising compounds within a database, and generating focussed libraries of predicted derivatives. A ligand-based virtual screening tool Investigational Novel Drug Discovery by Example (INDDEx) is used as the basis for a system of virtual reactions. The use of virtual reactions is estimated to open up a potential space of 1.21×1012 potential molecules. A de novo design algorithm known as Partial Logical-Rule Reactant Selection (PLoRRS) is introduced and incorporated into the INDDEx methodology. PLoRRS uses logical rules from the INDDEx model to select reactants for the de novo generation of potentially active products. The PLoRRS method is found to increase significantly the likelihood of retrieving molecules similar to known actives with a p-value of 0.016. Case studies demonstrate that the virtual reactions produce molecules highly similar to known actives, including known blockbuster drugs.
| S-EPMC4641463 | biostudies-literature
Project description:BMC Ecology showcases the winning entries from its second Ecology Image Competition. More than 300 individual images were submitted from an international array of research scientists, depicting life on every continent on earth. The journal's Editorial Board and guest judge Caspar Henderson outline why their winning selections demonstrated high levels of technical skill and aesthetic sense in depicting the science of ecology, and we also highlight a small selection of highly commended images that we simply couldn't let you miss out on.
| S-EPMC4236560 | biostudies-literature
Project description:Computer-assisted drug design (CADD) methods have greatly contributed to the development of new drugs. Among CADD methodologies, virtual screening (VS) can enrich the compound collection with molecules that have the desired physicochemical and pharmacophoric characteristics that are needed to become drugs. Many free tools are available for this purpose, but they are difficult to use and do not have a graphical user interface. Furthermore, several free tools must be used to carry out the entire VS process, requiring the user to process the results of one software program so that they can be used in another program, adding a potential source of human error. Moreover, some software programs require knowledge of advanced computational skills, such as programming languages. This context has motivated us to develop Molecular Architect (MolAr). MolAr is a workflow with a simple and intuitive interface that acts in an integrated and automated form to perform the entire VS process, from protein preparation (homology modeling and protonation state) to virtual screening. MolAr carries out VS through AutoDock Vina, DOCK 6, or a consensus of the two. Two case studies were conducted to demonstrate the performance of MolAr. In the first study, the feasibility of using MolAr for DNA-ligand systems was assessed. Both AutoDock Vina and DOCK 6 showed good results in performing VS in DNA-ligand systems. However, the use of consensus virtual screening was able to enrich the results. According to the area under the ROC curve and the enrichment factors, consensus VS was better able to predict the positions of the active ligands. The second case study was performed on 8 targets from the DUD-E database and 10 active ligands for each target. The results demonstrated that using the final ligand conformation provided by AutoDock Vina as an input for DOCK 6 improved the DOCK 6 ROC curves by up to 42% in VS. These case studies demonstrated that MolAr is capable conducting the VS process and is an easy-to-use and effective tool. MolAr is available for download free of charge at http: //www.drugdiscovery.com.br/software/.
| S-EPMC7114615 | biostudies-literature
Project description:BackgroundPersonalised instruction is increasingly recognised as crucial for efficacious learning today. Our seminal work delineates and elaborates on the principles, development and implementation of a specially-designed adaptive, virtual laboratory.AimsWe strived to teach laboratory skills associated with lactate dehydrogenase (LDH) enzyme kinetics to 2nd-year biochemistry students using our adaptive learning platform. Pertinent specific aims were to:(1)design/implement a web-based lesson to teach lactate dehydrogenase(LDH) enzyme kinetics to 2nd-year biochemistry students(2)determine its efficacious in improving students' comprehension of enzyme kinetics(3)assess their perception of its usefulness/manageability(vLab versus Conventional Tutorial).MethodsOur tools were designed using HTML5 technology. We hosted the program on an adaptive e-learning platform (AeLP). Provisions were made to interactively impart informed laboratory skills associated with measuring LDH enzyme kinetics. A series of e-learning methods were created. Tutorials were generated for interactive teaching and assessment.ResultsThe learning outcomes herein were on par with that from a conventional classroom tutorial. Student feedback showed that the majority of students found the vLab learning experience "valuable"; and the vLab format/interface "well-designed". However, there were a few technical issues with the 1st roll-out of the platform.ConclusionsOur pioneering effort resulted in productive learning with the vLab, with parity with that from a conventional tutorial. Our contingent discussion emphasises not only the cornerstone advantages, but also the shortcomings of the AeLP method utilised. We conclude with an astute analysis of possible extensions and applications of our methodology.
| S-EPMC4878458 | biostudies-literature
Project description:Chemotherapy of East Coast fever, a lymphoproliferative cancer-like disease of cattle causing significant economic losses in Africa, is largely dependent on the use of buparvaquone, a drug that was developed in the late 1980's. The disease is caused by the tick-borne protozoan pathogen Theileria parva. Buparvaquone can be used prophylactically and it is also active against tropical theileriosis, caused by the related parasite Theileria annulata. Recently, drug resistance was reported in T. annulata, and could occur in T. parva. Using a 3H-thymidine incorporation assay we screened 796 open source compounds from the Medicines for Malaria Venture (MMV) to discover novel chemicals with potential inhibitory activity to T. parva. We identified nine malaria box compounds and eight pathogen box compounds that inhibited the proliferation of F100TpM, a T. parva infected lymphocyte cell line. However, only two compounds, MMV008212 and MMV688372 represent promising leads with IC50 values of 0.78 and 0.61??M, respectively, and CC50 values?>?5??M. The remaining compounds exhibited a high degree of toxicity (CC50 values?<?1.09??M) on the proliferation of bovine peripheral blood mononuclear cells stimulated with concanavalin A. We also tested the anti-cancer drug, dasatinib, used in the chemotherapy of some leukemias. Dasatinib was as active and safe as buparvaquone in vitro, with an IC50 of 5 and 4.2?nM, respectively, and CC50?>?10??M. Our preliminary data suggest that it may be possible to repurpose compounds from the cancer field as well as MMV as novel anti-T. parva molecules.
| S-EPMC6376154 | biostudies-literature