A multi-reference poly-conformational method for in silico design, optimization, and repositioning of pharmaceutical compounds illustrated for selected SARS-CoV-2 ligands.

Background: This work presents a novel computational multi-reference poly-conformational algorithm for design, optimization, and repositioning of pharmaceutical compounds. Methods: The algorithm searches for candidates by comparing similarities between conformers of the same compound and identifies target compounds, whose conformers are collectively close to the conformers of each compound in the reference set. Reference compounds may possess highly variable MoAs, which directly, and simultaneously, shape the properties of target candidate compounds. Results: The algorithm functionality has been case study validated in silico, by scoring ChEMBL drugs against FDA-approved reference compounds that either have the highest predicted binding affinity to our chosen SARS-CoV-2 targets or are confirmed to be inhibiting such targets in-vivo. All our top scoring ChEMBL compounds also turned out to be either high-affinity ligands to the chosen targets (as confirmed in separate studies) or show significant efficacy, in-vivo, against those selected targets. In addition to method case study validation, in silico search for new compounds within two virtual libraries from the Enamine database is presented. The library's virtual compounds have been compared to the same set of reference drugs that we used for case study validation: Olaparib, Tadalafil, Ergotamine and Remdesivir. The large reference set of four potential SARS-CoV-2 compounds has been selected, since no drug has been identified to be 100% effective against the virus so far, possibly because each candidate drug was targeting only one, particular MoA. The goal here was to introduce a new methodology for identifying potential candidate(s) that cover multiple MoA-s presented within a set of reference compounds.

Patient- and Ventilator-Specific Modeling to Drive the Use and Development of 3D Printed Devices for Rapid Ventilator Splitting During the COVID-19 Pandemic

In the early days of the COVID-19 pandemic, there was a pressing need for an expansion of the ventilator capacity in response to the COVID19 pandemic. Reserved for dire situations, ventilator splitting is complex, and has previously been limited to patients with similar pulmonary compliances and tidal volume requirements. To address this need, we developed a system to enable rapid and efficacious splitting between two or more patients with varying lung compliances and tidal volume requirements. We present here a computational framework to both drive device design and inform patient-specific device tuning. By creating a patient- and ventilator-specific airflow model, we were able to identify pressure-controlled splitting as preferable to volume-controlled as well create a simulation-guided framework to identify the optimal airflow resistor for a given patient pairing. In this work, we present the computational model, validation of the model against benchtop test lungs and standard-of-care ventilators, and the methods that enabled simulation of over 200 million patient scenarios using 800,000 compute hours in a 72 h period. © 2022, The Author(s), under exclusive license to Springer Nature Switzerland AG.

Combating Viral Diseases in the Era of Systems Medicine.

Viruses can cause many diseases resulting in disabilities and death. Fortunately, advances in systems medicine enable the development of effective therapies for treating viral diseases, of vaccines to prevent viral infections, as well as of diagnostic tools to mitigate the risk and reduce the death toll. Characterizing the SARS-CoV-2 gene sequence and the role of its spike protein in infection informs development of small molecule drugs, antibodies, and vaccines to combat infection and complication, as well as to end the pandemic. Drug repurposing of small molecule drugs is a viable strategy to combat viral diseases; the key concepts include (1) linking a drug candidate's pharmacological network to its pharmacodynamic response in patients; (2) linking a drug candidate's physicochemical properties to its pharmacokinetic characteristics; and (3) optimizing the safe and effective dosing regimen within its therapeutic window. Computational integration of drug-induced signaling pathways with clinical outcomes is useful to inform selection of potential drug candidates with respect to safety and effectiveness. Key pharmacokinetic and pharmacodynamic principles for computational optimization of drug development include a drug candidate's Cminss/IC95 ratio, pharmacokinetic characteristics, and systemic exposure-response relationship, where Cminss is the trough concentration following multiple dosing. In summary, systems medicine approaches play a vital role in global success in combating viral diseases, including global real-time information sharing, development of test kits, drug repurposing, discovery and development of safe, effective therapies, detection of highly transmissible and deadly variants, and development of vaccines.

DeepABM: Scalable and Efficient Agent-Based Simulations Via Geometric Learning Frameworks-a Case Study for Covid-19 Spread and Interventions

We introduce DeepABM, a computational framework for agent-based modeling that leverages geometric message passing for simulating action and interactions over large agent populations. Using DeepABM allows scaling simulations to large agent populations in real-time and running them efficiently on GPU architectures. Using the DeepABM framework, we build DeepABM-COVID simulator to provide support for various non-pharmaceutical interventions (quarantine, exposure notification, vaccination, testing) for the COVID-19 pandemic, and can scale to populations of representative size in real-time on a GPU. DeepABM-COVID can model 200 million interactions (over 100,000 agents across 180 time-steps) in 90 seconds, and is made available online to help researchers with modeling and analysis of various interventions. We explain various components of the framework and discuss results from one research study to evaluate the impact of delaying the second dose of the COVID-19 vaccine in collaboration with clinical and public health experts. © 2021 IEEE.

CoFIM: A Computational Framework for Proteomic and Metabolomic Integrated Data Analysis

Motivation: Coronavirus disease (COVID-19) struck the world in late 2019 and caused millions of deaths worldwide as an infectious disease caused by the SARS-CoV-2 virus. An effective and early diagnosis is truly pivotal, and thus, many studies were initiated for that. The existing studies have some limitations such as only focusing on one type of omics data. The study aims to develop a computational model which studies COVID-19 with the integration of metabolomics and proteomics data, therefore reaching the goal of detecting the virus early in the stage. Methods: The computational framework for integrating multi-omics data (CoFIM) consists of two parts. The first part is a statistical analysis of datasets. In this study, a series of statistical analyses including univariate and multivariate analyses were conducted to identify a number of potential biomarkers after pulling the data of severe patients and non-severe patients from a proteomic and metabolomics dataset of sera samples of COVID-19 patients. The second part is a machine learning model that was conducted to predict a patient's disease progression and provide more insightful information to understand the disease. Results: CoFIM integrates both proteomic and metabolomics data and provides a customizable and scalable framework to analyze the multi-omics data. CoFIM is demonstrated on the COVID-19 dataset and a number of biomarkers were detected. Several new protein biomarkers (IGKV1-12, PCOLCE, PGLYRP2, PCYOX1, LUM, IGHV1-46) were detected. We believe CoFIM will be widely used for multi-omics data analysis. © 2021 ACM.

Modeling of Crisis Periods in Stock Markets

We exploit a recent computational framework to model and detect financial crises in stock markets, as well as shock events in cryptocurrency markets, which are characterized by a sudden or severe drop in prices. Our method manages to detect all past crises in the French industrial stock market starting with the crash of 1929, including financial crises after 1990 (e.g. dot-com bubble burst of 2000, stock market downturn of 2002), and all past crashes in the cryptocurrency market, namely in 2018, and also in 2020 due to covid-19. We leverage copulae clustering, based on the distance between probability distributions, in order to validate the reliability of the framework;we show that clusters contain copulae from similar market states such as normal states, or crises. Moreover, we propose a novel regression model that can detect successfully all past events using less than 10% of the information that the previous framework requires. We train our model by historical data on the industry assets, and we are able to detect all past shock events in the cryptocurrency market. Our tools provide the essential components of our software framework that offers fast and reliable detection, or even prediction, of shock events in stock and cryptocurrency markets of hundreds of assets. © 2021, Springer Nature Switzerland AG.

A simplified model to estimate COVID19 transport in enclosed spaces

Airborne pathogen respiratory droplets are the primary route of COVID19 transmission, which are released from infected people. The strength and amplitude of a release mechanism strongly depend on the source mode, including respiration, speech, sneeze, and cough. This study aims to develop a simplified model for evaluation of spreading range (length) in sneeze and cough modes using the results of Eulerian-Lagrangian CFD model. The Eulerian computational framework is first validated with experimental data, and then a high-fidelity Lagrangian CFD model is employed to monitor various scale particles' trajectory, evaporation, and lingering persistency. A series of Eulerian-Lagrangian CFD simulations is conducted to generate a database of bioaerosol release spectrum for the release modes in various thermal conditions of an enclosed space. Eventually, a correlation fitted over the data to offer a simplified airborne pathogen spread model. The simplified model can be applied as a source model for design and decision-making about ventilation systems, occupancy thresholds, and disease transmission risks in enclosed spaces. © 2021 Institute of Physics Publishing. All rights reserved.

Strategies for Vaccine Prioritization and Mass Dispensing.

We propose a system that helps decision makers during a pandemic find, in real time, the mass vaccination strategies that best utilize limited medical resources to achieve fast containments and population protection. Our general-purpose framework integrates into a single computational platform a multi-purpose compartmental disease propagation model, a human behavior network, a resource logistics model, and a stochastic queueing model for vaccination operations. We apply the modeling framework to the current COVID-19 pandemic and derive an optimal trigger for switching from a prioritized vaccination strategy to a non-prioritized strategy so as to minimize the overall attack rate and mortality rate. When vaccine supply is limited, such a mixed vaccination strategy is broadly effective. Our analysis suggests that delays in vaccine supply and inefficiencies in vaccination delivery can substantially impede the containment effort. Employing an optimal mixed strategy can significantly reduce the attack and mortality rates. The more infectious the virus, the earlier it helps to open the vaccine to the public. As vaccine efficacy decreases, the attack and mortality rates rapidly increase by multiples; this highlights the importance of early vaccination to reduce spreading as quickly as possible to lower the chances for further mutations to evolve and to reduce the excessive healthcare burden. To maximize the protective effect of available vaccines, of equal importance are determining the optimal mixed strategy and implementing effective on-the-ground dispensing. The optimal mixed strategy is quite robust against variations in model parameters and can be implemented readily in practice. Studies with our holistic modeling framework strongly support the urgent need for early vaccination in combating the COVID-19 pandemic. Our framework permits rapid custom modeling in practice. Additionally, it is generalizable for different types of infectious disease outbreaks, whereby a user may determine for a given type the effects of different interventions including the optimal switch trigger.