Alternatives Research & Development Foundation to Support Research on COVID-19, Aiming for Advancement in Non-animal Methods of Drug Discovery

By | News, Research

Pharmaceutical companies across the globe are racing to introduce clinically tested and approved therapeutic drugs that fight COVID-19 virus to market. As is typical in drug discovery research, animals have played a critical role in the development and testing of COVID-19 therapeutics. A proposal by U-M Professor Rudy J. Richardson, Dow Professor Emeritus of Toxicology, Professor Emeritus of Environmental Health Sciences, and Associate Professor Emeritus of Neurology at the University of Michigan, titled “Discovering host factor inhibitors in silico for SARS-CoV-2 entry and replication” has been awarded funding to identify compounds that bind to human proteins that facilitate entry and/or replication of the SARS-CoV-2 virus. Awarded, in part, because of its potential to develop alternative methods to advance science and replace or reduce animal use, this research will employ in silico ligand protein docking to discover existing drugs (repurposing) and/or new drug candidates capable of inhibiting host proteins involved in infection pathways for the COVID-19 virus, SARS-CoV-2.

Protein docking targets include four serine hydrolases. Using these targets, researchers will reversibly dock approximately 40,000 ligands from the Binding Database comprising FDA-approved drugs along with serine protease and PLA2 inhibitors, including organoboron compounds. Then, covalent docking will be conducted on a ligand subset containing pharmacophores capable of covalently binding serine hydrolases. Consensus ranking from four docking programs will be used to generate a penultimate list of candidate compounds. Those showing high predicted potency against off-target serine hydrolases will be excluded. The final list of compounds will be made publicly available for further evaluation in bioassays.

Professor Richardson’s grant, awarded by the Alternatives Research & Development Foundation, is a part of the ARDF’s 2020 Open Grants program, funding research projects that develop alternate methods to advance science and replace or reduce animal use. Although the immediate goal of this computational study supports the identification or development of a COVID-19 vaccine, the long-range vision is to advance computational and in vitro approaches to eliminate animal use from drug discovery for humans and other species. 

MICDE Affiliated Faculty member Rudy J. Richardson is a Dow Professor Emeritus of Toxicology and Professor Emeritus of Environmental Health Sciences within the School of Public Health, and Associate Professor Emeritus of Neurology within the Medical School at the University of Michigan.

MICDE funds wide-ranging computational discovery in galactic formation, drug discovery, bacterial biofilm colonies and turbulence simulations

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Since 2017 the Michigan Institute for Computational Discovery & Engineering (MICDE) Catalyst Grants program has funded a wide spectrum of cutting-edge research that combines science, engineering, mathematics and computer science. This year the program will fund four new projects that continue this tradition: Prof. Aaron Frank (Chemistry) and his group will spearhead efficient strategies to rapidly develop treatments for emerging diseases– a need made more compelling by the current COVID-19 Pandemic. Their approach combines generative artificial intelligence models and molecular docking to rapidly explore the space of chemical structures and generate target-specific virtual libraries for drug discovery. Prof. Marisa Eisenberg (Epidemiology, Mathematics, and Complex Systems) and Prof. Alexander Rickard’s (Epidemiology) groups will develop novel computational techniques to study biofilm architectures.  Biofilms are complex assemblages of microbial cells that form on almost any natural and man-made surface. They cause several debilitating diseases, and can even damage machinery and equipment, elevating the understanding of their behaviour to a critical need. Prof. Oleg Gnedin (Astronomy) will develop novel techniques to tailor the mathematical initial conditions from which to simulate chosen regions of the universe. The resulting insights will help uncover the origins of our own galaxy, the Milky Way. Finally, Prof. Aaron Towne (Mechanical Engineering) will advance the modeling of complex, turbulent flows and other large-scale systems in engineering science. His research will enable orders of magnitude of acceleration in the computation of extremely large scale flows in a number of engineering systems.

“These four projects have the potential to catalyze and  reorient the directions of their research fields by developing and harnessing powerful paradigms of computational science”, said Krishna Garikipati, Professor of Mechanical Engineering and of Mathematics, and MICDE’s Director. “MICDE’s mission is to lead the advances in computational science research by bringing together interdisciplinary teams at U of M, and these projects embody that vision.” 

More about MICDE’s catalyst grant program and the projects can be found at micde.umich.edu/catalyst.

Microsoft AI for Health Program to support an AI-facilitated Optimization Framework for Improving COVID-19 Testing

By | News, Research

With the recent resurgence of COVID-19 infections, testing has become central to an integrated, global response to the pandemic. Accurate, effective, and efficient testing can lead to early detection and prompt an agile response by public health authorities. Strategic testing systems are critical for providing data that will inform disease prevention, preparation, and intervention. MICDE Associate Director and Associate Professor of Industrial and Operations Engineering and of Civil and Environmental Engineering, Siqian Shen, has recently published an article pin-pointing a number of pivotal operations research and industrial engineering tools that can be brought to  the fight against COVID-19. One of the key lessons from her research is the importance of expanding the availability of COVID-19 testing and making the resulting data transparent to the public as anonymized, summary statistics. This enables informed decision making by individuals, public health officials, and governments.  

Based on these high-impact findings, Professor Shen is striding ahead to design a comprehensive COVID-19 testing framework to efficiently serve the urgent needs of diverse population groups . A grant from Microsoft’s AI for Health program, part of the AI for Good initiative, will provide credits to use Microsoft’s Azure service.  With this cyber resource, Professor Shen and her team will integrate and coordinate decision-making models and data analytics tools that they have developed for testing on a Cloud-based platform. In addition, their AI framework is dynamic, and collects daily infection data to improve testing-related decisions. Such a platform could have significant impacts on three major problems that exist with current testing design strategies:

1) Where to locate testing facilities and how to allocate test kits and other resources.
2) How to effectively triage different population groups through effective appointment scheduling.
3) How to visualize real-time testing capacities to better inform the public and serve ad-hoc needs of patients. 

Prof. Shen’s research will integrate AI techniques with optimization to dynamically refine existing testing design methods for gathering and analyzing data from unexplored populations and regions around the globe. The development and refinement of these new models with the support of Microsoft Azure will create a transparent, data-informed testing system that will allow public health and government authorities to make agile, data-driven decisions to aid in the prevention, preparation, intervention, and management of COVID-19 and other outbreaks of infectious diseases.

Siqian Shen is a  Professor of Industrial and Operations Engineering, and of Civil and Environmental Engineering at the University of Michigan, an Associate Director of the Michigan Institute for Computational Discovery & Engineering, and an affiliated faculty member in the Michigan Institute for Data Science. Her research group works on both theoretical and applied aspects of problems by combining stochastic programming, integer programming, network optimization,  machine learning and statistics.

What is the right model? Different MRIO models yield very different carbon footprints estimates in China

By | Research

Appropriate accounting of greenhouse gas emissions is the first step to assign mitigation responsibilities and develop effective mitigation strategies. Consistent methods are required to fairly assess a region’s impact on climate change. Two leading reasons for the existence of different accounting systems are the political pressures, and the actual costs of climate mitigation to local governments. At the international level there has been consensus, and global environmentally extended multi-regional input-output (EE-MRIO) models that capture the interdependence of and their environmental impacts have been constructed.  However in China, the largest greenhouse gas emitter, where accurate interregional trade-related emission accounts are critical to develop mitigation strategies and monitor progresses at the regional level, this information is sporadic and inconsistent. Prof. Ming Xu from the School of Environment and Sustainability, and his research group, analyzed the available data from China, which dates back to 2012. They showed that the results varied wildly depending on the MRIO model used. For example, they found two MRIO models differed as much as 208 metric tons in a single region, which is equivalent to the emissions of Argentina, United Arab Emirates, or the Netherlands. Their results show the need to prioritize future efforts to harmonize greenhouse gas emissions accounting within China.

Ming Xu is an Associate Professor in the School for Environment and Sustainability and in the Department of Civil and Environmental Engineering at the University of Michigan, Ann Arbor. His research focuses on the broad fields of sustainable engineering and industrial ecology. 

Read the full article.

Modeling the transmission of infectious aerosols

By | Feature, Research

Inhalation of micron-sized droplets represents the dominant transmission mechanism for influenza and rhinovirus, and recent research shows that it is likely also the case for the novel coronavirus.  Increasing evidence suggests that the transmission of infectious aerosols is more complex than previously thought. Coughing, sneezing and even talking yield a gaseous flow field near the infected person that is dynamic and turbulent in nature. Existing models commonly employed in simulations of aerosol transmission attempt to represent the effect of turbulence using random walk models that are often phenomenological in nature, employing adjustable parameters and inherently assuming the turbulent fluctuations ‘felt’ by a droplet do not depend upon direction. To design physics-informed guidelines to minimize the spread of this virus, improved predictive modeling capabilities for effectively tracking the aerosol paths are needed. Dr. Aaron M. Lattanzi and Prof. Jesse Capecelatro, from Mechanical Engineering and MICDE are tackling this problem by focusing on mathematical modeling of aerosol dispersion. They derived analytical solutions for the mean-squared-displacement resulting from systems of stochastic differential equations. A key element of their methodology is that the solution connects stochastic theory inputs to statistics present in high-fidelity simulations or experiments, providing a framework for developing improved models.

Simple simulation of aerosol dispersion from a single-point source. The grey, cone-like surface is the approximation using Force Langevin (FL) theory and the colored particles are from integration of Newton’s equations with stochastic drag forces.

Prof. Capecelatro’s research group develops physics-based models and numerical algorithms to leverage supercomputers for prediction and optimization of the complex flows relevant to energy and the environment. The main focus of their research involves developing robust and scalable numerical tools to investigate the multiphysics and multiscale phenomena under various flow conditions, like those that they study here. They recently submitted their findings to the Journal of Fluid Mechanics, and are continuing to work on this problem hoping it will help understand the transmission of COVID-19 and therefore help optimize current guidelines.