Discovery of anti-2019-nCoV agents from Chinese patent drugs 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, rutin, baicalin, glycyrrhizin, mulberroside A, puerarin, orientin, amygdalin, and ilexgenin A, can directly bind to both host cell target ACE2 receptor and viral target main protease, indicating their potential for 2019-nCoV treatment.


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 14 out of 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 14 CPDs were collected as the ligands, and all the ligands were in PDBQT format.

Results and Discussion
A total of 14 marketed CPDs (bold line in Table 1) containing 63 herbs used for the treatment of respiratory diseases were selected. Totally we docked 52 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.
Notably, artemisinin, berberine, rutin, glycyrrhizin, chlorogenic acid, baicalin, cholic acid, hyodeoxycholic acid, and puerarin are commercially available with good supply, suggesting a future new drug development is of necessity. In addition, the results of Table 5 in combination of the literature data indicated the natural sources of these active compounds with relatively high content. Basically, around 19 compounds are present in natural sources more than 1% (g/g), which are respectively hesperidin, baicalin, glycyrrhizin, puerarin, amygdalin, paeoniflorin, berberine, arctiin, forsythiaside A, chlorogenic acid, geniposide, magnolol, lobetyolin, pulegone, citrulline, L-menthol, 6-gingerol, rutin (source plant: Potentilla chinensis), and harpagide (source plant: Ajuga pantantha) ( Table 5). This information in combination with the docking results suggests that these plants or herbs or their extracts with enriched active compounds might be valuable for fighting against 2019-nCoV. Although the other herbs or CPDs are not found to be active toward 2019-nCoV, this doesn't mean that they are not useful for NCP because only limited compounds in herbs were selected which couldn't exclude more compounds or their analogues in herbs of CPDs are active. In addition, the principles of formulating Chinese herbal prescription include eliminating evil and strengthening the body resistance, therefore, we couldn't exclude that these CPDs do work against NCP via regulating immune system. Further efforts on docking of the structures from the rest 24 CPDs are undergoing. Validation of these docking results is also undergoing.   Decanoy acetaldehyde -3.9 -4.9 -8.8