Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease in vitro (preprint)

Human infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause coronavirus disease 19 (COVID-19) and there is currently no cure. The 3C-like protease (3CLpro), a highly conserved protease indispensable for replication of coronaviruses, is a promising target for development of broad-spectrum antiviral drugs. To advance the speed of drug discovery and development, we investigated the inhibition of SARS-CoV-2 3CLpro by natural products derived from Chinese traditional medicines. Baicalin and baicalein were identified as the first non-covalent, non-peptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system. Remarkably, the binding mode of baicalein with SARS-CoV-2 3CLpro determined by X-ray protein crystallography is distinctly different from those of known inhibitors. Baicalein is perfectly ensconced in the core of the substrate-binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a "shield" in front of the catalytic dyad to prevent the peptide substrate approaching the active site. The simple chemical structure, unique mode of action, and potent antiviral activities in vitro, coupled with the favorable safety data from clinical trials, emphasize that baicalein provides a great opportunity for the development of critically needed anti-coronaviral drugs.

Theoretical Study of the anti-NCP Molecular Mechanism of Traditional Chinese Medicine Lianhua-Qingwen Formula (LQF) (preprint)

Due to the good clinical efficacy in treating Novel Coronavirus Pneumonia (NCP) resulted from SARS-CoV-2, as the traditional Chinese medicine(TCM) prescription, Lianhua Qingwen Formula (LQF) was composed into the Diagnosis and Treatment Programs of 2019 New Coronavirus Pneumonia (from fourth to seventh editions) formulated by the National Health Commission of China. Aiming to prevent and treat viral influenza, LQF was patented from 2003 in China, and passed the Phase II clinical trial by FDA in the United States in 2015. However, the molecular mechanism of LQF anti SARS-CoV-2 pneumonia is still not clear. It is shown that the docking scores of three components in LQF including Rutin, Forsythoside E, and Hyperoside to main protease of SARS-CoV-2 are very large as -9.1, -9.0 and -8.7 kcal/mol, respectively, which are even better than those of Lopinavir at -7.3 kcal/mol. Importantly, the binding modes between active compounds and protein were verified via molecular dynamics (MD) simulation and calculation all the binding free energies at MM-PBSA level. Note that these donor-acceptor systems were stabilized by non-polar interactions including hydrogen bonds and hydrophobic interactions. At last, from the constructed component-target-pathway network, it is shown that the components in LQF are related important pathways to improve the human immunity such as T cell, B cell receptor signaling, natural killer cell mediated cytotoxicity, as well as anti inflammatory pathways including Fc epsilon RI, ErbB, MAPK signaling and so on. The present investigation represents the first report on the molecular mechanism of LQF as NCP inhibitor