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Item Use of stem cell-derived cardiomyocyte and nasal epithelium models to establish a multi-tissue model platform to validate repurposed drugs against sars-cov-2 infection(2024-05) Agarwal, VintiThe novel coronavirus disease (COVID-19) and any future coronavirus outbreaks will require more affordable, effective and safe treatment options to complement current ones such as Paxlovid. Drug repurposing can be a promising approach if we are able to find a rapid, robust and reliable way to down-select and screen candidates using in silico and in vitro approaches. With repurposed drugs, ex vivo models could offer a rigorous route to human clinical trials with less time invested into nonclinical animal (in vivo) studies. We have previously shown the value of commercially available ex vivo/3D airway and alveolar tissue models, and this paper takes this further by developing and validating human nasal epithelial model and embryonic stem cells derived cardiomyocyte model. Five shortlisted candidates (fluvoxamine, everolimus, pyrimethamine, aprepitant and sirolimus) were successfully compared with three control drugs (remdesivir, molnupiravir, nirmatrelvir) when tested against key variants of the SARS-CoV-2 virus including Delta and Omicron, and we were able to reconfirm our earlier finding that fluvoxamine can induce antiviral efficacy in combination with other drugs. Scalability of this high-throughput screening approach has been demonstrated using a liquid handling robotic platform for future ‘Disease-X’ outbreaks.Item A clustering and graph deep learning-based framework for COVID-19 drug repurposing(Elsevier, 2024-09) Agarwal, Vinti; Deepa, P.R.Drug repurposing (or repositioning) is the process of finding new therapeutic uses for drugs already approved by drug regulatory authorities (e.g., the Food and Drug Administration (FDA) and Therapeutic Goods Administration (TGA)) for other diseases. This involves analysing the interactions between different biological entities, such as drug targets (genes/proteins and biological pathways) and drug properties, to discover novel drug–target or drug–disease relations. Machine learning and deep learning models have successfully analysed complex heterogeneous data with applications in the biomedical domain, and have also been used for drug repurposing. This study presents a novel unsupervised machine learning framework that utilizes a graph-based autoencoder for multi-feature type clustering on heterogeneous drug data. The dataset consists of 438 drugs, of which 224 are under clinical trials for COVID-19 (category A). The rest are systematically filtered to ensure the safety and efficacy of the treatment (category B). The framework solely relies on reported drug data, including its pharmacological properties, chemical/physical properties, interaction with the host, and efficacy in different publicly available COVID-19 assays. Our machine-learning framework revealed three clusters of interest and provided recommendations featuring the top 15 drugs for COVID-19 drug repurposing, which were shortlisted based on the predicted clusters that were dominated by category A drugs. Our framework can be extended to support other datasets and drug repurposing studies with the availability of our open-source code.Item Unsupervised machine learning framework for discriminating major variants of concern during COVID-19(ARXIV, 2022-10) Agarwal, VintiDue to high mutation rates, COVID-19 evolved rapidly, and several variants such as Alpha, Gamma, Delta, Beta, and Omicron emerged with altered viral properties like the severity of the disease caused, transmission rates, etc. These variants burdened the medical systems worldwide and created a massive impact on the world economy as each had to be studied and dealt with in its specific ways. Unsupervised machine learning methods have the ability to compress, characterize, and visualize unlabelled data. In this paper, we present a framework that utilizes unsupervised machine learning methods to discriminate and visualize the associations between major COVID-19 variants based on their genome sequences. These methods comprise a combination of selected dimensionality reduction and clustering techniques. The framework processes the RNA sequences by performing a k-mer analysis on the data and then compares the results from different dimensionality reduction methods including: Principal Component Analysis (PCA), t-Distributed Stochastic Neighbour Embedding (t-SNE), and Uniform Manifold Approximation Projection (UMAP). Our framework also employs agglomerative hierarchical clustering to visualize the mutational differences among major variants of concern and country-wise mutational differences for a particular variant (Delta and Omicron) using dendrograms. We also provide country-wise mutational differences for selected variants via dendrograms. We conclude that the proposed framework can effectively distinguish between the major variants and hence can be used for the identification of emerging variants in the future.Item Systematic Down-Selection of Repurposed Drug Candidates for COVID-19(IJMS, 2022) Agarwal, VintiSARS-CoV-2 is the cause of the COVID-19 pandemic which has claimed more than 6.5 million lives worldwide, devastating the economy and overwhelming healthcare systems globally. The development of new drug molecules and vaccines has played a critical role in managing the pandemic; however, new variants of concern still pose a significant threat as the current vaccines cannot prevent all infections. This situation calls for the collaboration of biomedical scientists and healthcare workers across the world. Repurposing approved drugs is an effective way of fast-tracking new treatments for recently emerged diseases. To this end, we have assembled and curated a database consisting of 7817 compounds from the Compounds Australia Open Drug collection. We developed a set of eight filters based on indicators of efficacy and safety that were applied sequentially to down-select drugs that showed promise for drug repurposing efforts against SARS-CoV-2. Considerable effort was made to evaluate approximately 14,000 assay data points for SARS-CoV-2 FDA/TGA-approved drugs and provide an average activity score for 3539 compounds. The filtering process identified 12 FDA-approved molecules with established safety profiles that have plausible mechanisms for treating COVID-19 disease. The methodology developed in our study provides a template for prioritising drug candidates that can be repurposed for the safe, efficacious, and cost-effective treatment of COVID-19, long COVID, or any other future disease. We present our database in an easy-to-use interactive interface (CoviRx that was also developed to enable the scientific community to access to the data of over 7000 potential drugs and to implement alternative prioritisation and down-selection strategies.Item CoviRx: A User-Friendly Interface for Systematic Down-Selection of Repurposed Drug Candidates for COVID-19(MDPI, 2022) Agarwal, Vintilthough various vaccines are now commercially available, they have not been able to stop the spread of COVID-19 infection completely. An excellent strategy to get safe, effective, and affordable COVID-19 treatments quickly is to repurpose drugs that are already approved for other diseases. The process of developing an accurate and standardized drug repurposing dataset requires considerable resources and expertise due to numerous commercially available drugs that could be potentially used to address the SARS-CoV-2 infection. To address this bottleneck, we created the CoviRx.org platform. CoviRx is a user-friendly interface that allows analysis and filtering of large quantities of data, which is onerous to curate manually for COVID-19 drug repurposing. Through CoviRx, the curated data have been made open source to help combat the ongoing pandemic and encourage users to submit their findings on the drugs they have evaluated, in a uniform format that can be validated and checked for integrity by authenticated volunteers. This article discusses the various features of CoviRx, its design principles, and how its functionality is independent of the data it displays. Thus, in the future, this platform can be extended to include any other disease beyond COVID-19