TOWARDS UNDERSTANDING MODE-OF-ACTION OF TRADITIONAL MEDICINES BY USING IN SILICO TARGET PREDICTION

Traditional medicines (TM) have been used for centuries to treat illnesses, but in many cases their modes-of-action (MOAs) remain unclear. Given the increasing data of chemical ingredients of traditional medicines and the availability of large-scale bioactivity data linking chemical structures to activities against protein targets, we are now in a position to propose computational hypotheses for the MOAs using in silico target prediction. The MOAs were established from supporting literature. The in silico target prediction, which is based on the “Molecular Similarity Principle”, was modelled via two models: a Naïve Bayes Classifier and a Random Forest Classifier. Chapter 2 discovered the relationship of 46 traditional Chinese medicine (TCM) therapeutic action subclasses by mapping them into a dendrogram using the predicted targets. Overall, the most frequent top three enriched targets/pathways were immune-related targets such as tyrosine-protein phosphatase non-receptor type 2 (PTPN2) and digestive system such as mineral absorption. Two major protein families, G-protein coupled receptor (GPCR), and protein kinase family contributed to the diversity of the bioactivity space, while digestive system was consistently annotated pathway motif. Chapter 3 compared the chemical and bioactivity space of 97 anti-cancer plants’ compounds of TCM, Ayurveda and Malay traditional medicine. The comparison of the chemical space revealed that benzene, anthraquinone, flavone, sterol, pentacyclic triterpene and cyclohexene were the most frequent scaffolds in those TM. The annotation of the bioactivity space with target classes showed that kinase class was the most significant target class for all groups. From a phylogenetic tree of the anti-cancer plants, only eight pairs of plants were phylogenetically related at either genus, family or order level. Chapter 4 evaluated synergy score of pairwise compound combination of Shexiang Baoxin Pill (SBP), a TCM formulation for myocardial infarction. The score was measured from the topological properties, pathway dissimilarity and mean distance of all the predicted targets of a combination on a representative network of the disease. The method found four synergistic combinations, ginsenoside Rb3 and cholic acid, ginsenoside Rb2 and ginsenoside Rb3, ginsenoside Rb3 and 11-hydroxyprogesterone and ginsenoside Rb2 and ginsenoside Rd agreed with the experimental results. The modulation of androgen receptor, epidermal growth factor and caspases were proposed for the synergistic actions. Altogether, in silico target prediction was able to discover the bioactivity space of different TMs and elucidate the MOA of multiple formulations and two major health concerns: cancer and myocardial infarction. Hence, understanding the MOA of the traditional medicine could be beneficial in providing testable hypotheses to guide towards finding new molecular entities

Study on open science: The general state of the play in Open Science principles and practices at European life sciences institutes

Nowadays, open science is a hot topic on all levels and also is one of the priorities of the European Research Area. Components that are commonly associated with open science are open access, open data, open methodology, open source, open peer review, open science policies and citizen science. Open science may a great potential to connect and influence the practices of researchers, funding institutions and the public. In this paper, we evaluate the level of openness based on public surveys at four European life sciences institute

Automatic Extraction and Assessment of Entities from the Web

The search for information about entities, such as people or movies, plays an increasingly important role on the Web. This information is still scattered across many Web pages, making it more time consuming for a user to find all relevant information about an entity. This thesis describes techniques to extract entities and information about these entities from the Web, such as facts, opinions, questions and answers, interactive multimedia objects, and events. The findings of this thesis are that it is possible to create a large knowledge base automatically using a manually-crafted ontology. The precision of the extracted information was found to be between 75–90 % (facts and entities respectively) after using assessment algorithms. The algorithms from this thesis can be used to create such a knowledge base, which can be used in various research fields, such as question answering, named entity recognition, and information retrieval

A study assessing the characteristics of big data environments that predict high research impact: application of qualitative and quantitative methods

BACKGROUND: Big data offers new opportunities to enhance healthcare practice. While researchers have shown increasing interest to use them, little is known about what drives research impact. We explored predictors of research impact, across three major sources of healthcare big data derived from the government and the private sector. METHODS: This study was based on a mixed methods approach. Using quantitative analysis, we first clustered peer-reviewed original research that used data from government sources derived through the Veterans Health Administration (VHA), and private sources of data from IBM MarketScan and Optum, using social network analysis. We analyzed a battery of research impact measures as a function of the data sources. Other main predictors were topic clusters and authors’ social influence. Additionally, we conducted key informant interviews (KII) with a purposive sample of high impact researchers who have knowledge of the data. We then compiled findings of KIIs into two case studies to provide a rich understanding of drivers of research impact. RESULTS: Analysis of 1,907 peer-reviewed publications using VHA, IBM MarketScan and Optum found that the overall research enterprise was highly dynamic and growing over time. With less than 4 years of observation, research productivity, use of machine learning (ML), natural language processing (NLP), and the Journal Impact Factor showed substantial growth. Studies that used ML and NLP, however, showed limited visibility. After adjustments, VHA studies had generally higher impact (10% and 27% higher annualized Google citation rates) compared to MarketScan and Optum (p<0.001 for both). Analysis of co-authorship networks showed that no single social actor, either a community of scientists or institutions, was dominating. Other key opportunities to achieve high impact based on KIIs include methodological innovations, under-studied populations and predictive modeling based on rich clinical data. CONCLUSIONS: Big data for purposes of research analytics has grown within the three data sources studied between 2013 and 2016. Despite important challenges, the research community is reacting favorably to the opportunities offered both by big data and advanced analytic methods. Big data may be a logical and cost-efficient choice to emulate research initiatives where RCTs are not possible

Timely and reliable evaluation of the effects of interventions: a framework for adaptive meta-analysis (FAME)

Most systematic reviews are retrospective and use aggregate data AD) from publications, meaning they can be unreliable, lag behind therapeutic developments and fail to influence ongoing or new trials. Commonly, the potential influence of unpublished or ongoing trials is overlooked when interpreting results, or determining the value of updating the meta-analysis or need to collect individual participant data (IPD). Therefore, we developed a Framework for Adaptive Metaanalysis (FAME) to determine prospectively the earliest opportunity for reliable AD meta-analysis. We illustrate FAME using two systematic reviews in men with metastatic (M1) and non-metastatic (M0)hormone-sensitive prostate cancer (HSPC)

Development and implementation of in silico molecule fragmentation algorithms for the cheminformatics analysis of natural product spaces

Computational methodologies extracting specific substructures like functional groups or molecular scaffolds from input molecules can be grouped under the term “in silico molecule fragmentation”. They can be used to investigate what specifically characterises a heterogeneous compound class, like pharmaceuticals or Natural Products (NP) and in which aspects they are similar or dissimilar. The aim is to determine what specifically characterises NP structures to transfer patterns favourable for bioactivity to drug development. As part of this thesis, the first algorithmic approach to in silico deglycosylation, the removal of glycosidic moieties for the study of aglycones, was developed with the Sugar Removal Utility (SRU) (Publication A). The SRU has also proven useful for investigating NP glycoside space. It was applied to one of the largest open NP databases, COCONUT (COlleCtion of Open Natural prodUcTs), for this purpose (Publication B). A contribution was made to the Chemistry Development Kit (CDK) by developing the open Scaffold Generator Java library (Publication C). Scaffold Generator can extract different scaffold types and dissect them into smaller parent scaffolds following the scaffold tree or scaffold network approach. Publication D describes the OngLai algorithm, the first automated method to identify homologous series in input datasets, group the member structures of each group, and extract their common core. To support the development of new fragmentation algorithms, the open Java rich client graphical user interface application MORTAR (MOlecule fRagmenTAtion fRamework) was developed as part of this thesis (Publication E). MORTAR allows users to quickly execute the steps of importing a structural dataset, applying a fragmentation algorithm, and visually inspecting the results in different ways. All software developed as part of this thesis is freely and openly available (see https://github.com/JonasSchaub)

Integrative approaches to high-throughput data in lymphoid leukemias (on transcriptomes, the whole-genome mutational landscape, flow cytometry and gene copy-number alterations)

Within this thesis I developed a new approach for the analysis and integration of heterogeneous leukemic data sets applicable to any high-throughput analysis including basic research. All layers are stored in a semantic graph which facilitates modifications by just adding edges (relationships/attributes) and nodes (values/results) as well as calculating biological consensus and clinical correlation. The front-end is accessible through a GUI (graphical user interface) on a Java-based Semantic Web server. I used this framework to describe the genomic landscape of T-PLL (T-cell prolymphocytic leukemia), which is a rare (~0.6/million) mature T-cell malignancy with aggressive clinical course, notorious treatment resistance, and generally low overall survival. We have conducted gene expression and copy-number profiling as well as NGS (next-generation sequencing) analyses on a cohort comprising 94 T-PLL cases. TCL1A (T-cell leukemia/lymphoma 1A) overexpression and ATM (Ataxia Telangiectasia Mutated) impairment represent central hallmarks of T-PLL, predictive for patient survival, T-cell function and proper DNA damage responses. We identified new chromosomal lesions, including a gain of AGO2 (Argonaute 2, RISC Catalytic Component; 57.14% of cases), which is decisive for the chromosome 8q lesion. While we found significant enrichments of truncating mutations in ATM mut/no del (p=0.01365), as well as FAT (FAT Atypical Cadherin) domain mutations in ATM mut/del (p=0.01156), JAK3 (Janus Kinase 3) mut/ATM del cases may represent another tumor lineage. Using whole-transcriptome sequencing, we identified novel structural variants affecting chromosome 14 that lead to the expression of a TCL1A-TCR (T-cell receptor) fusion transcript and a likely degradated TCL1A protein. Two clustering approaches of normal T-cell subsets vs. leukemia gene expression profiles, as well as immunophenotyping-based agglomerative clustering and TCR repertoire reconstruction further revealed a restricted, memory-like T-cell phenotype. This is to date the most comprehensive, multi-level, integrative study on T-PLL and it led to an evolutionary disease model and a histone deacetylase-inhibiting / double strand break-inducing treatment that performs better than the current standard of chemoimmunotherapy in preclinical testing

INTEGRATING CHEMICAL, BIOLOGICAL AND PHYLOGENETIC SPACES OF AFRICAN NATURAL PRODUCTS TO UNDERSTAND THEIR THERAPEUTIC ACTIVITY

INTEGRATING CHEMICAL, BIOLOGICAL AND PHYLOGENETIC SPACES OF AFRICAN NATURAL PRODUCTS TO UNDERSTAND THEIR THERAPEUTIC ACTIVITY Fatima Magdi Hamza Baldo This research aims to utilise ligand-based target prediction to (i) understand the mechanism of action of African natural products (ANPs), (ii) help identify patterns of phylogenetic use in African traditional medicine and (iii) elucidate the mechanism of action of phenotypically active small molecules and natural products with anti-trypanosomal activity. In Chapter 2 the objective was to utilise ligand-based target prediction to understand the mechanism of action of natural products (NPs) from African medicinal plants used against cancer. The Random Forest classifier used in this work compares the similarity of the input compounds from the natural product dataset with compound-target combinations in the training set. The more similar they are in structure, the more likely they are to modulate the same target. Natural products from plants used against cancer in Africa were predicted to modulate targets and pathways directly associated with the disease, thus understanding their mechanism of action e.g. “flap endonuclease 1” and “Mcl-1”. The “Keap1-Nrf2 Pathway” and “apoptosis modulation by HSP70”, two pathways previously linked to cancer (which are not currently targeted by marketed drugs, but have been of increasing interest in recent years) were predicted to be modulated by ANPs. In Chapter 3, we aimed to identify phylogenetic patterns in medicinal plant use and the role this plays in predicting medicinal activity. We combined chemical, predicted target and phylogenetic information of the natural products to identify patterns of use for plant families containing plant species used against cancer in African, Malay and Indian (Ayurveda) traditional medicine. Plant families that are close phylogenetically were found to produce similar natural products that act on similar targets regardless of their origin. Additionally, phylogenetic patterns were identified for African traditional plant families with medicinal species used against cancer, malaria and human African trypanosomiasis (HAT). We identified plant families that have more medicinal species than would statistically be expected by chance and rationalised this by linking their activity to their unique phyto-chemistry e.g. the napthyl-isoquinoline alkaloids, uniquely produced by Acistrocladaceae and Dioncophyllaceae, are responsible for anti-malarial and anti-trypanosome activity. In Chapter 4, information from target prediction and experimentally validated targets was combined with orthologue data to predict targets of phenotypically active small molecules and natural products screened against Trypanosoma brucei. The predicted targets were prioritised based on their essentiality for the survival of the T. brucei parasite. We predicted orthologues of targets that are essential for the survival of the trypanosome e.g. glycogen synthase kinase 3 (GSK3) and rhodesain. We also identified the biological processes predicted to be perturbed by the compounds e.g. “glycolysis”, “cell cycle”, “regulation of symbiosis, encompassing mutualism through parasitism” and “modulation of development of symbiont involved in interaction with host”. In conclusion, in silico target prediction can be used to predict protein targets of natural products to understand their molecular mechanism of action. Phylogenetic information and phytochemical information of medicinal plants can be integrated to identify plant families with more medicinal species than would be expected by chance