Improved electrocatalysts for the oxygen reduction reaction (ORR) are critical for the advancement of fuel cell technologies. Herein, we report a series of 11 soluble iron porphyrin ORR electrocatalysts that possess turnover frequencies (TOFs) from 3 s^–1 to an unprecedented value of 2.2 × 10⁶ s^–1. These TOFs correlate with the ORR overpotential, which can be modulated by changing the E_1/2 of the catalyst using different ancillary ligands, by changing the solvent and solution acidity, and by changing the catalyst’s protonation state. The overpotential is well-defined for these homogeneous electrocatalysts by the E_1/2 of the catalyst and the proton activity of the solution. This is the first such correlation for homogeneous ORR electrocatalysis, and it demonstrates that the remarkably fast TOFs are a consequence of high overpotential. The correlation with overpotential is surprising since the turnover limiting steps involve oxygen binding and protonation, as opposed to turnover limiting electron transfer commonly found in Tafel analysis of heterogeneous ORR materials. Computational studies show that the free energies for oxygen binding to the catalyst and for protonation of the superoxide complex are in general linearly related to the catalyst E_1/2, and that this is the origin of the overpotential correlations. This analysis thus provides detailed understanding of the ORR barriers. The best catalysts involve partial decoupling of the influence of the second coordination sphere from the properties of the metal center, which is suggested as new molecular design strategy to avoid the limitations of the traditional scaling relationships for these catalysts.

Despite the recent availability of vaccines against the acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the search for inhibitory therapeutic agents has assumed importance especially in the context of emerging new viral variants. In this paper, we describe the discovery of a novel noncovalent small-molecule inhibitor, MCULE-5948770040, that binds to and inhibits the SARS-Cov-2 main protease (M^pro) by employing a scalable high-throughput virtual screening (HTVS) framework and a targeted compound library of over 6.5 million molecules that could be readily ordered and purchased. Our HTVS framework leverages the U.S. supercomputing infrastructure achieving nearly 91% resource utilization and nearly 126 million docking calculations per hour. Downstream biochemical assays validate this M^pro inhibitor with an inhibition constant (K_i) of 2.9 μM (95% CI 2.2, 4.0). Furthermore, using room-temperature X-ray crystallography, we show that MCULE-5948770040 binds to a cleft in the primary binding site of M^pro forming stable hydrogen bond and hydrophobic interactions. We then used multiple μs-time scale molecular dynamics (MD) simulations and machine learning (ML) techniques to elucidate how the bound ligand alters the conformational states accessed by M^pro, involving motions both proximal and distal to the binding site. Together, our results demonstrate how MCULE-5948770040 inhibits M^pro and offers a springboard for further therapeutic design.