ABSTRACT
As a theoretically rigorous and accurate method, FEP-ABFE (Free Energy Perturbation-Absolute Binding Free Energy) calculations showed great potential in drug discovery, but its practical application was difficult due to high computational cost. To rapidly discover antiviral drugs targeting SARS-CoV-2 M- pro and TMPRSS2, we performed FEP-ABFE-based virtual screening for similar to 12,000 protein-ligand binding systems on a new generation of Tianhe supercomputer. A task management tool was specifically developed for automating the whole process involving more than 500,000 MD tasks. In further experimental validation, 50 out of 98 tested compounds showed significant inhibitory activity towards M- pro , and one representative inhibitor, dipyridamole, showed remarkable outcomes in subsequent clinical trials. This work not only demonstrates the potential of FEP-ABFE in drug discovery but also provides an excellent starting point for further development of anti-SARS-CoV-2 drugs. Besides, similar to 500 TB of data generated in this work will also accelerate the further development of FEP-related methods.
ABSTRACT
A mixed antigen coating method was designed to optimize the method for detecting the titer of the immune serum to inactivated SARS-CoV-2 vaccine, which based on the traditional single antigen coating.The authors determined the optimal coating concentration of the single antigen first by the checkerboard method, then combined two kinds of antigen and obtained coating concentration of the mixed antigen.The best combination of mixed coating antigen contains the whole-coronavirus antigen with total protein concentration of 25 ng/well and the recombinant new coro-navirus S1 protein antigen with protein concentration of 50 ng/well.This method can be used to detect all antibody-specific titers in serum effectively, especially serum containing high-level S protein-specific antibodies.