The Drug Repurposing Strategy in the Exscalate4CoV Project: Raloxifene Clinical Trials

Drug repurposing is a cost-effective process to identify therapeutic candidates during a medical crisis or pandemic. The supercomputing platform, EXaSCale smArt pLatform Against paThogEns for CoronaVirus (EXSCALATE4CoV;E4C), was used to identify drug candidates for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. E4C identified raloxifene as having great therapeutic potential, confirmed by in vitro data, which led to the progression of clinical trials to assess its efficacy. Raloxifene met the primary virologic endpoint in the treatment of early mild coronavirus disease 2019 (COVID-19), and although additional clinical trials are needed to confirm these results, there is evidence in support of in silico drug repurposing to provide cost-effective and rapid drug screening to identify treatment options for the pandemic and future pandemics. © 2023, The Author(s), under exclusive license to Springer Nature Switzerland AG.

A European Drug-Discovery Platform: From In Silico to Experimental Validation

The COVID-19 pandemic highlighted an urgent need for streamlined drug development processes. Enhanced virtual screening methods could expedite drug discovery via rapid screening of large virtual compound libraries to identify high-priority drug candidates. The EXSCALATE4CoV (EXaSCale smArt pLatform Against paThogEns for CoronaVirus) consortium (E4C) research team developed EXSCALATE (EXaSCale smArt pLatform Against paThogEns), the most complex screening simulation to date, containing a virtual library of >500 billion compounds and a high-throughput docking software, LiGen (Ligand Generator). Additionally, E4C developed a smaller virtual screen of a "safe-in-man” drug library to identify optimal candidates for drug repurposing. To identify compounds targeting SARS-CoV-2, EXSCALATE performed >1 trillion docking simulations to optimize the probability of identifying successful drug candidates. Ligands identified in simulations underwent subsequent in vitro experimentation to determine drug candidates that have anti-SARS-CoV-2 agency and have probable in-human efficacy. While many compound candidates were validated to have anti-SARS-CoV-2 properties, raloxifene had the best outcome and subsequently demonstrated efficacy in a phase 2 clinical trial in patients with early mild-to-moderate COVID-19, providing proof of concept that the in silico approaches used here are a valuable resource during emergencies. After its emergence in 2019, the SARS-CoV-2 coronavirus spread internationally at a rapid pace, leading to the designation of COVID-19 as a pandemic in March 2020. In addition to a devastating impact on public health, COVID-19 has resulted in extensive negative social and economic effects in every corner of the globe. When the pandemic arrived, the medical and scientific communities identified an urgent need to establish more rapid therapeutic and vaccine development processes for COVID-19. However, it was clear that any new measures needed to be implemented in a way that also supported rapid mobilization to fight potential future pandemics. Therapeutic discovery is a complicated and prolonged process, often taking 10–15 years to complete all stages, and typically involves a linear workflow starting with in silico investigations, followed by increasingly complex and correspondingly expensive in vitro, in vivo, and clinical studies. In the context of the pandemic, the importance of the in silico stage increased because of the capacity of exascale computational methods to identify and prioritize small molecule (and biological) agents with the greatest therapeutic potential. Better in silico-generated starting points for drug-discovery efforts increase the likelihood of success in downstream laboratory-based experimental stages and can contribute to vitally needed reductions in costs and time to market for new therapies. © 2023, The Author(s), under exclusive license to Springer Nature Switzerland AG.

Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets.

Mycobacterium tuberculosis (M. tb), the causative agent of TB, is a recalcitrant pathogen that is rife around the world, latently infecting approximately a quarter of the worldwide population. The asymptomatic status of the dormant bacteria escalates to the transmissible, active form when the host's immune system becomes debilitated. The current front-line treatment regimen for drug-sensitive (DS) M. tb strains is a 6-month protocol involving four different drugs that requires stringent adherence to avoid relapse and resistance. Poverty, difficulty to access proper treatment, and lack of patient compliance contributed to the emergence of more sinister drug-resistant (DR) strains, which demand a longer duration of treatment with more toxic and more expensive drugs compared to the first-line regimen. Only three new drugs, bedaquiline (BDQ) and the two nitroimidazole derivatives delamanid (DLM) and pretomanid (PMD) were approved in the last decade for treatment of TB-the first anti-TB drugs with novel mode of actions to be introduced to the market in more than 50 years-reflecting the attrition rates in the development and approval of new anti-TB drugs. Herein, we will discuss the M. tb pathogenesis, current treatment protocols and challenges to the TB control efforts. This review also aims to highlight several small molecules that have recently been identified as promising preclinical and clinical anti-TB drug candidates that inhibit new protein targets in M. tb.

Drug Repurposing for SARS-COV-2 Using Molecular Docking

Drug repurposing is an unconventional approach that is used to investigate new therapeutic aids of existing and shelved drugs. Recent advancement in technologies and the availability of the data of genomics, proteomics, transcriptomics, etc., and with the accessibility of large and reliable database resources, there are abundantly of opportunities to discover drugs by drug repurposing in an efficient manner. The recent pandemic of SARS-COV-2, that caused the death of 6,245,750 human beings to date, has tremendously increase the exceptional usage of bioinformatics tools in interpreting the molecular characterizations of viral infections. In this paper, we have employed various bioinformatics tools such as AutoDock-Vina, PyMol etc. We have found a leading drug candidate Cepharanthine (CEP) that has shown better results and effectiveness than recently used antiviral drug candidates such as Favipiravir, IDX184, Remedesivir, Ribavirin and etc. This paper has analyzed CEP's potential therapeutic importance as a drug of choice in managing COVID-19 cases. It is anticipated that proposed study would be beneficial for researchers and medical practitioners in handling SARS-CoV-2 and its variant related diseases. © 2022 IEEE.

In silico study to find a potent inhibitor, Vilazodone, to cure COVID-19 using molecular docking

The pandemic caused by the coronavirus SARS-COVID-2 has had devastating impact on the world. It has caused a significant number of deaths across the world. Fast spread and lack of vaccine prompted academia to adopt new, fast and reliable methodologies to design new drugs. A combined approach of direct drug design and indirect drug design has been used for molecular docking. In the study, we found a compound, Vilazodone, with a binding energy of -8.40 kcal/mol. The druglikeness properties of this compound are investigated through SWISS ADMET analysis. In this in-silico study, we confirmed this compound is a potential drug candidate against SARS-CoV-2.However, in-vitro and in-vivo studies are required to prove its efficacy. © 2022 IEEE.

Discovery of Triple Inhibitors of Both SARS-CoV-2 Proteases and Human Cathepsin L.

One inhibitor of the main SARS-CoV-2 protease has been approved recently by the FDA, yet it targets only SARS-CoV-2 main protease (Mpro). Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases involved in SARS-CoV-2 replication, including Mpro, SARS-CoV-2 papain-like protease (PLpro), and human cathepsin L. The use of thiuram disulfide and dithiobis-(thioformate) covalent inhibitor warheads was inspired by an idea to find a better alternative than disulfiram, an approved treatment for chronic alcoholism that is currently in phase 2 clinical trials against SARS-CoV-2. Our goal was to find more potent inhibitors that target both viral proteases and one essential human protease to reduce the dosage, improve the efficacy, and minimize the adverse effects associated with these agents. We found that compounds coded as RI175, RI173, and RI172 were the most potent inhibitors in an enzymatic assay against SARS-CoV-2 Mpro, SARS-CoV-2 PLpro, and human cathepsin L, with IC50s of 300, 200, and 200 nM, which is about 5-, 19-, and 11-fold more potent than disulfiram, respectively. In addition, RI173 was tested against SARS-CoV-2 in a cell-based and toxicity assay and was shown to have a greater antiviral effect than disulfiram. The identified compounds demonstrated the promising potential of thiuram disulfide or dithiobis-(thioformate) as a reactive functional group in small molecules that could be further developed for treatment of the COVID-19 virus or related variants.

Scope of computational biology and bioinformatics towards the discovery of potential therapeutic agents against viral diseases

Computational biology and bioinformatics resources provide a cutting-edge platform for the screening and development of novel therapeutic agents against probable targets of emerging viral diseases. Emerging viral infections such as COVID-19, Ebola, Nipha andMiddle East respiratory syndrome are some of the potential public health threats reported with high mortality and morbidity. The infections caused by these viruses were recently considered as acute onset immune dysrhythmia syndrome. The altered monocytic, cytokines and chemokines balances observed in several emerging viral infections lead to the acute respiratory distress and multiinflammatory syndromes [1]. Recent studies suggested that many countries were unable to manage the drastic and unexpected onset of these viral outbreaks and such a scenario adversely affected the global economy [2]. There are limited vaccines currently available for most of these viral infections and the vaccine development strategies are extremely tedious and complex. In addition, there are no approved drugs available for most of the emerging viral infections. For example, although the use of non toxic concentrations of 2-deoxy-D-glucose (2-DG), a glucose analog that inhibits the activity of phosphoglucoisomerase in the glycolytic pathway of SARS-CoV-2 is suggested to be one of the promising therapeutic agents for COVID-19, the successful application of this drug is yet to be confirmed [3]. Thus, the present editorial briefly outlines the scope of bioinformatics and computational biology toward the discovery of potential therapeutic agents against various viral diseases.

Self-Supervised Learning with Heterogeneous Graph Neural Network for COVID-19 Drug Recommendation

The emergence and spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have created an enormous socioeconomic impact. Although there are several promising drug candidates in clinical trials, none of them are approved yet. Thus, the drug repositioning approach may help to overcome the current pandemic. However, the sparse dataset of COVID-19 limits the accuracy of existing drug repositioning. To overcome this problem, we propose a novel drug repositioning framework (named Drug2Cov). Drug2Cov can learn an effective representation via integrating self-supervised learning with sparse data. Meanwhile, Drug2Cov uses a heterogeneous graph neural network to capture the complex interaction between viruses, targets, and drugs that enhance the accuracy of drug repositioning. The experimental results demonstrate the effectiveness and feasibility of our proposed Drug2Cov framework. Source code and dataset are freely available at https://github.com/lhf3291109/Drug2Cov. © 2021 IEEE.

Design, synthesis and biological evaluation of 1,5-disubstituted α-amino tetrazole derivatives as non-covalent inflammasome-caspase-1 complex inhibitors with potential application against immune and inflammatory disorders.

Compounds targeting the inflammasome-caspase-1 pathway could be of use for the treatment of inflammation and inflammatory diseases. Previous caspase-1 inhibitors were in great majority covalent inhibitors and failed in clinical trials. Using a mixed modelling, computational screening, synthesis and in vitro testing approach, we identified a novel class of non-covalent caspase-1 non cytotoxic inhibitors which are able to inhibit IL-1ß release in activated macrophages in the low µM range, in line with the best activities observed for the known covalent inhibitors. Our compounds could form the basis of further optimization towards potent drugs for the treatment of inflammation and inflammatory disorders including also dysregulated inflammation in Covid 19.

SARS-CoV-2 and SARS-CoV: Virtual screening of potential inhibitors targeting RNA-dependent RNA polymerase activity (NSP12).

Since the outbreak of severe acute respiratory syndrome (SARS) in 2003, the harm caused by coronaviruses to the world cannot be underestimated. Recently, a novel coronavirus (severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2]) initially found to trigger human severe respiratory illness in Wuhan City of China in 2019, has infected more than six million people worldwide by 21 June 2020, and which has been recognized as a public health emergency of international concern as well. And the virus has spread to more than 200 countries around the world. However, the effective drug has not yet been officially licensed or approved to treat SARS-Cov-2 and SARS-Cov infection. NSP12-NSP7-NSP8 complex of SARS-CoV-2 or SARS-CoV, essential for viral replication and transcription, is generally regarded as a potential target to fight against the virus. According to the NSP12-NSP7-NSP8 complex (PDB ID: 7BW4) structure of SARS-CoV-2 and the NSP12-NSP7-NSP8 complex (PDB ID: 6NUR) structure of SARS-CoV, NSP12-NSP7 interface model, and NSP12-NSP8 interface model were established for virtual screening in the present study. Eight compounds (Nilotinib, Saquinavir, Tipranavir, Lonafarnib, Tegobuvir, Olysio, Filibuvir, and Cepharanthine) were selected for binding free energy calculations based on virtual screening and docking scores. All eight compounds can combine well with NSP12-NSP7-NSP8 in the crystal structure, providing drug candidates for the treatment and prevention of coronavirus disease 2019 and SARS.

Potential roles of medicinal plants for the treatment of viral diseases focusing on COVID-19: A review.

The whole world is entangled by the coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), people are dying in thousands each day, and without an actual medication, it seems not possible for the bringing this global health crisis to a stop. Natural products have been in constant use since ancient times and are proven by time to be effective. Crude extract or pure compounds isolated from medicinal plants and/or herbs such as Artemisia annua, Agastache rugosa, Astragalus membranaceus, Cassia alata, Ecklonia cava, Gymnema sylvestre, Glycyrrhizae uralensis, Houttuynia cordata, Lindera aggregata, Lycoris radiata, Mollugo cerviana, Polygonum multiflorum, Pyrrosia lingua, Saposhnikoviae divaricate, Tinospora cordifolia etc. have shown promising inhibitory effect against coronavirus. Several molecules, including acacetin, amentoflavone, allicin, blancoxanthone, curcumin, daidzein, diosmin, epigallocatechin-gallate, emodin, hesperidin, herbacetin, hirsutenone, iguesterin, jubanine G, kaempferol, lycorine, pectolinarin, phloroeckol, silvestrol, tanshinone I, taxifolin, rhoifolin, xanthoangelol E, zingerol etc. isolated from plants could also be potential drug candidates against COVID-19. Moreover, these could also show promising inhibitory effects against influenza-parainfluenza viruses, respiratory syncytial virus, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have reported 93 antiviral drug candidates which could be a potential area of research in drug discovery.

Coronavirus (COVID - 19): Chemical Entities of Biological Interest.

Virus, a sub-microscopic infectious agent that replicates only inside the living cells of a host, causes viral infection. Currently, the immediate imperative is to control the combat against novel coronavirus outbreak caused by the COVID-19 virus, which started in China and spread all over the world. The domain of travelling has emphasized COVID-19 virus prevention as a serious issue for the safety of human beings. The exponential rise in the number of corona patients is a matter of concern for governing bodies of various countries in spite of countless cooperative efforts put in by citizens, organizations and government. India is now among the top worst hit nation in terms of the spread of COVID-19 pandemic. The present article reviews various state-of-art medicinal approaches available that are presently used to control the spread of coronavirus pandemic.

Comparative transcriptome analysis of SARS-CoV, MERS-CoV, and SARS-CoV-2 to identify potential pathways for drug repurposing.

The ongoing COVID-19 pandemic caused by the coronavirus, SARS-CoV-2, has already caused in excess of 1.25 million deaths worldwide, and the number is increasing. Knowledge of the host transcriptional response against this virus and how the pathways are activated or suppressed compared to other human coronaviruses (SARS-CoV, MERS-CoV) that caused outbreaks previously can help in the identification of potential drugs for the treatment of COVID-19. Hence, we used time point meta-analysis to investigate available SARS-CoV and MERS-CoV in-vitro transcriptome datasets in order to identify the significant genes and pathways that are dysregulated at each time point. The subsequent over-representation analysis (ORA) revealed that several pathways are significantly dysregulated at each time point after both SARS-CoV and MERS-CoV infection. We also performed gene set enrichment analyses of SARS-CoV and MERS-CoV with that of SARS-CoV-2 at the same time point and cell line, the results of which revealed that common pathways are activated and suppressed in all three coronaviruses. Furthermore, an analysis of an in-vivo transcriptomic dataset of COVID-19 patients showed that similar pathways are enriched to those identified in the earlier analyses. Based on these findings, a drug repurposing analysis was performed to identify potential drug candidates for combating COVID-19.

Anti-SARS-CoV Natural Products With the Potential to Inhibit SARS-CoV-2 (COVID-19).

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), known to cause the disease COVID-19, was declared a pandemic in early 2020. The objective of this review was to collate information regarding the potential of plants and natural products to inhibit coronavirus and targets associated with infection in humans and to highlight known drugs, which may have potential activity against SARS-CoV-2. Due to the similarity in the RNA genome, main proteases, and primary host receptor between SARS-CoV and SARS-CoV-2, a review was conducted on plants and secondary metabolites, which have shown activity against SARS-CoV. Numerous scientific reports on the potential of plants and secondary metabolites against SARS-CoV infection were found, providing important information on their possible activity against SARS-CoV-2. Based on current literature, 83 compounds have been identified with the potential to inhibit COVID-19. The most prominent selectivity was found for the alkaloid, lycorine, the lignan, savinin, and the abietane terpenoid, 8-beta-hydroxyabieta-9(11),13-dien-12-one with selectivity index values greater than 945, 667, and 510, respectively. Plants and their secondary metabolites, with activity against targets associated with the SARS-CoV infection, could provide valuable leads for the development into drugs for the novel SARS-CoV-2. The prospects of using computational methods to screen secondary metabolites against SARS-CoV targets are briefly discussed, and the drawbacks have been highlighted. Finally, we discuss plants traditionally used in Southern Africa for symptoms associated with respiratory viral infections and influenza, such as coughs, fever, and colds. However, only a few of these plants have been screened against SARS-CoV. Natural products hold a prominent role in discovering novel therapeutics to mitigate the current COVID-19 pandemic; however, further investigations regarding in vitro, in vivo, pre-clinical, and clinical phases are still required.