Discovery of anti-2019-nCoV agents from 38 Chinese patent drugs toward respiratory diseases via docking screening

The 2019 novel coronavirus (2019-nCoV) causes novel coronavirus pneumonia (NCP). Given that approved drug repurposing becomes a common strategy to quickly find antiviral treatments, a collection of FDA-approved drugs can be powerful resources for new anti-NCP indication discoveries. In addition to synthetic compounds, Chinese Patent Drugs (CPD), also play a key role in the treatment of virus related infections diseases in China. Here we compiled major components from 38 CPDs that are commonly used in the respiratory diseases and docked them against two drug targets, ACE2 receptor and viral main protease. According to our docking screening, 10 antiviral components, including hesperidin, saikosaponin A, rutin, corosolic acid, verbascoside, baicalin, glycyrrhizin, mulberroside A, cynaroside, and bilirubin, can directly bind to both host cell target ACE2 receptor and viral target main protease. In combination of the docking results, the natural abundance of the substances, and botanical knowledge, we proposed that artemisinin, rutin, glycyrrhizin, cholic acid, hyodeoxycholic acid, puerarin, oleanic acid, andrographolide, matrine, codeine, morphine, chlorogenic acid, and baicalin (or Yinhuang Injection containing chlorogenic acid and baicalin) might be of value for clinical trials during a 2019-nCov outbreak. Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 23 February 2020 doi:10.20944/preprints202002.0254.v2


Introduction
The 2019 novel coronavirus (2019-nCoV), named as the Wuhan coronavirus [the pneumonia caused by it is now named as novel coronavirus pneumonia (NCP)], is a positive-sense, single-strand RNA coronavirus (1). Up to date, global infections of 2019-nCoV surge past 40,000 (WHO website). Given that drug repurposing is the common strategy to search antiviral treatments, several approved drugs were reported to benefit patients (2). Besides synthetic compounds, natural products, especially Chinese Patent Drug (CPD), also play a key role in the treatment of virus related infections diseases in China. Although the mechanisms of CPDs might be associated with immune regulation, we focus on their antiviral properties. In this study. we compiled major components from 38 CPDs that are commonly used in the respiratory diseases and docked them against two drug targets, ACE2 receptor and viral main protease.
Like severe acute respiratory syndrome-related coronavirus (SARS-CoV), the 2019-nCoV attach to host cells through S protein and angiotensin converting enzyme 2 (ACE2) receptor interaction (3). The catalytic inhibitor of ACE2 receptor is likely to induce a conformational change of ACE2, therefore blocking the interaction between S protein and ACE2 receptor (4). S protein of 2019-nCoV is not currently available but the structure of ACE2 receptor is well-known (5). Thus ACE2 receptor was selected to quickly identify entry inhibitors of 2019-nCoV using marketed CPDs-derived natural products.
In addition to entry inhibitors, the replication inhibitors are also good strategies for antiviral drug discovery and development (6). Given that 2019-nCoV is a (+)SS RNA virus, its main protease is likely to be required to mediate viral replication and transcription through extensive cleavage of two replicase polyproteins. Therefore inhibition of viral main protease might block virus replication (7). Up to date, Rao et al reported the crystal structure of M protease of 2019-nCoV (PDB: 6LU7) and several drug repurposing docking screening studies were reported. We herein docked natural product database to main protease to look for antiviral replication agents.
Due to the limited time and lack of the available 2019-nCoV in hand, it is impossible to develop novel compounds against 2019-nCoV by biological screening. We here used docking screening to identify natural products from marketed CPDs that inhibit both virus entry and replication, therefore providing a potential prevention/treatment alternative against 2019-nCoV.

Material and Methods
The major components of each herb in the selected 38 CPDs were collected as the ligands, and all the ligands were in PDBQT format.

Results and Discussion
A total of 38 marketed CPDs (bold line in Table 1) containing 93 herbs used for the treatment of respiratory diseases were selected. Totally we docked 95 components (Table 2) and the top 10 hits were summarized in Table 3. All of them provide good binding affinities against both two targets. The key residues for each ligand binding were also summarized in Table 4.