Preprint Article Version 2 Preserved in Portico This version is not peer-reviewed

Discovery of Multi-Target-Directed Ligands by Targeting Host-specific SARS-CoV-2’s Structurally Conserved Main Protease

Version 1 : Received: 5 April 2020 / Approved: 6 April 2020 / Online: 6 April 2020 (15:35:33 CEST)
Version 2 : Received: 8 April 2020 / Approved: 9 April 2020 / Online: 9 April 2020 (05:13:05 CEST)

A peer-reviewed article of this Preprint also exists.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in the current COVID-19 pandemic. Worldwide this disease has infected around 1.5 million individuals with a mortality rate ranging from 5 to 10%. It has also imposed extreme challenges on global health, economy, and social behavior. Due to the unavailability of therapeutics, several efforts are going on in the drug discovery to control the SARS-CoV-2 viral infection. The main protease (MPro) plays a critical role in viral replication and maturation, thus can serve as the primary drug target. To understand the structural evolution of MPro, we have performed phylogenetic and SSN analysis, that depicted divergence of Coronaviridae MPro in five clusters specific to viral hosts. This clustering was also corroborated with the comparison of MPro structures. Furthermore, it has been observed that backbone and binding site conformations are conserved despite variation in some of the residues. This conservation can be exploited to repurpose available viral protease inhibitors against SARS-CoV-2 MPro. In agreement with this, we performed screening of the custom-made library of ~7100 molecules including active ingredients present in the Ayurvedic anti-tussive medicines, anti-viral phytochemicals and synthetic anti-virals against SARS-CoV-2 MPro as the primary target. We identified several natural molecules that strongly binds to SARS-CoV-2 MPro among which top seven molecules are d-Viniferin, Myricitrin, Taiwanhomoflavone A, Lactucopicrin 15-oxalate, Nympholide A, Biorobin and Phyllaemblicin B. Most of the predicted lead molecules are from Vitis vinifera, also reported for anti-tussive and/or antiviral activities. These molecules also showed strong binding with other main targets RdRp and hACE-2. We anticipate that our approach for identification of multi-target-directed ligand will provide new avenues for drug discovery against SARS-CoV-2 infection.


coronavirus; COVID-19; hACE-2; MPro; multi-target-directed ligand; protease inhibito; RdRp; SARS-CoV-2 virus


Biology and Life Sciences, Biology and Biotechnology

Comments (1)

Comment 1
Received: 9 April 2020
Commenter: Rakesh Joshi
Commenter's Conflict of Interests: Author
Comment: 1. Phytochemical library is further enriched with the reported and predicted antiviral molecules
2. Docking analysis is extended for newly added molecules
3. Figure 5 is revised
4. Paragraph discussing about homology of MPro and RdRP with human proteins has been added in section 2.4
5. Authors list has been updated
+ Respond to this comment

We encourage comments and feedback from a broad range of readers. See criteria for comments and our Diversity statement.

Leave a public comment
Send a private comment to the author(s)
* All users must log in before leaving a comment
Views 0
Downloads 0
Comments 1
Metrics 0

Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.