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ABSTRACT: The rapid spread of SARS-CoV-2 has spurred the scientific world into action for therapeutics to help minimize fatalities from COVID-19. Molecular modeling is combating the current global pandemic through the traditional process of drug discovery, but the slow turnaround time for identifying leads for antiviral drugs, analyzing structural effects of genetic variation in the evolving virus, and targeting relevant virus-host protein interactions is still a great limitation during an acute crisis. The first component of drug discovery - the structure of potential drugs and the target proteins - has driven functional insight into biology ever since Watson, Crick, Franklin, and Wilkins solved the structure of DNA. What could we do with structural models of host and virus proteins and small molecule therapeutics? We can further enrich structure with dynamics for discovery of new surface sites exposed by fluctuations to bind drugs and peptide therapeutics not revealed by a static structural model. These “cryptic” binding sites offer new leads in drug discovery but will only yield fruit if they can be assessed rapidly for binding affinity for new small molecule drugs. We offer physics-inspired data-driven models to: 1) extend the chemical space of new drugs beyond those available; 2) create reliable scoring functions to evaluate drug binding affinities to cryptic binding sites of COVID-19 targets; 3) accelerate computation of binding affinities by training machine learning models; and 4) closing the loop of design and evaluation to bias the distribution of new drug candidates towards desired metrics enabled by the C3 AI Suite. Teresa Head-Gordon - The simultaneous revolutions in energy, molecular biology, nanotechnology, and advanced scientific computing is giving rise to new interdisciplinary research opportunities in theoretical and computational chemistry. The research interests of the Teresa Head-Gordon lab embraces this large scope of science drivers through the development of general computational models and methodologies applied to molecular liquids, macromolecular assemblies, protein biophysics, and homogeneous, heterogeneous catalysis and biocatalysis. She has a continued and abiding interest in the development and application of complex chemistry models, accelerated sampling methods, coarse graining, and multiscale techniques, analytical and semi-analytical solutions to the Poisson-Boltzmann Equation, and advanced self-consistent field (SCF) solvers and SCF-less methods for many-body physics. The methods and models developed in her lab are widely disseminated through many community software codes that scale on high performance computing platforms.
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