ABSTRACT
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.
ABSTRACT
The coronavirus disease 2019 pandemic not only precipitated a digital revolution but also led to one of the largest scientific collaborative open-source initiatives. The EXaSCale smArt pLatform Against paThogEns for CoronaVirus (EXSCALATE4CoV) consortium, led by Dompé farmaceutici S.p.A., brought together 18 global organizations to counter international pandemics more rapidly and efficiently. The consortium also partnered with Nanome, an extended reality software company whose software facilitates the visualization, modification, and simulation of molecules via augmented reality, mixed reality, and virtual reality applications. To characterize the molecular structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to identify promising drug targets, the EXSCALATE4CoV team utilized methods such as homology modeling, molecular dynamics simulations, high-throughput virtual screening, docking, and other computational procedures. Nanome provided analysis of those computational procedures and supplied virtual reality headsets to help scientists better understand and interact with the molecular dynamics and key chemical interactions of SARS-CoV-2. Nanome's collaborative ideation platform enables scientific breakthroughs across research institutions in the fight against the coronavirus pandemic and other diseases. © 2023, The Author(s), under exclusive license to Springer Nature Switzerland AG.
ABSTRACT
In the last 2 years, the SARS-CoV-2 (COVID-19) pandemic demonstrated that rapid response to outbreaks with readily effective treatments represents a primary health and societal priority. At the same time, we became conscious that technological resources are often not used in the most efficient manner. The LIGATE and REpurposing MEDIcines For All (REMEDI4ALL) projects started on the large-scale mobilization efforts of the EXaSCale smArt pLatform Against paThogEns (Exscalate4Cov) project with the aim to apply cutting-edge technologies in drug discovery, sustain the fight against future pandemics, and promote the everyday fight against rare diseases. In particular, the LIGATE project, using the drug-discovery platform Exscalate, intends to boost the virtual screening of drug campaigns at an extreme scale in terms of performance and streamline the drug-development process. The aim of the REMEDI4ALL project is to collect sciQ1entific expertise and innovative technology platforms for the repurposing of medicines to treat rare diseases or other pathologic conditions with no current therapy. © 2023, The Author(s), under exclusive license to Springer Nature Switzerland AG.
ABSTRACT
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.
ABSTRACT
Exascale computing has been a dream for ages and is close to becoming a reality that will impact how molecular simulations are being performed, as well as the quantity and quality of the information derived for them. We review how the biomolecular simulations field is anticipating these new architectures, making emphasis on recent work from groups in the BioExcel Center of Excellence for High Performance Computing. We exemplified the power of these simulation strategies with the work done by the HPC simulation community to fight Covid-19 pandemics. This article is categorized under:Data Science > Computer Algorithms and ProgrammingData Science > Databases and Expert SystemsMolecular and Statistical Mechanics > Molecular Dynamics and Monte-Carlo Methods.
ABSTRACT
In response to the COVID-19 pandemic, the Exascale Computing Project’s (ECP) Interoperable Design of Extreme-scale Application Software (IDEAS) productivity team launched the panel series Strategies for Working Remotely to facilitate informal, cross-organizational dialog in the absence of face-to-face meetings. In a time of pandemic, organizations increasingly need to reach across perceived boundaries to learn from each other, so that we can move beyond stand-alone silos to more connected multidisciplinary and multi-organizational configurations. The present paper argues that the unplanned transition to remote work, overuse of electronic communication, and need to unlearn habits associated with an overreliance on face-to-face, created unique opportunities to learn from the situation and accelerate cross-institutional cooperation and collaboration through online community dialog facilitated by informal panel discussions. Recommendations for facilitating online panel discussions to foster cross-organizational dialog are provided by applying the Simulation Experience Design Method. © 2022, The Author(s), under exclusive license to Springer Nature Switzerland AG.