Discovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in the current COVID-19 pandemic. Worldwide this disease has infected over 2.5 million individuals with a mortality rate ranging from 5 to 10%. There are several efforts going on in the drug discovery to control the SARS-CoV-2 viral infection. The main protease (M^Pro) plays a critical role in viral replication and maturation, thus can serve as the primary drug target. To understand the structural evolution of M^Pro, we have performed phylogenetic and Sequence Similarity Network analysis, that depicted divergence of Coronaviridae M^Pro in five clusters specific to viral hosts. This clustering was corroborated with the comparison of M^Pro structures. Furthermore, it has been observed that backbone and binding site conformations are conserved despite variation in some of the residues. These attributes can be exploited to repurpose available viral protease inhibitors against SARS-CoV-2 M^Pro. In agreement with this, we performed screening of ∼7100 molecules including active ingredients present in the Ayurvedic anti-tussive medicines, anti-viral phytochemicals and synthetic anti-virals against SARS-CoV-2 M^Pro as the primary target. We identified several natural molecules like δ-viniferin, myricitrin, taiwanhomoflavone A, lactucopicrin 15-oxalate, nympholide A, afzelin, biorobin, hesperidin and phyllaemblicin B that strongly binds to SARS-CoV-2 M^Pro. Intrestingly, these molecules also showed strong binding with other potential targets of SARS-CoV-2 infection like viral receptor human angiotensin-converting enzyme 2 (hACE-2) and RNA dependent RNA polymerase (RdRp). We anticipate that our approach for identification of multi-target-directed ligand will provide new avenues for drug discovery against SARS-CoV-2 infection.

Communicated by Ramaswamy H. Sarma

Keywords:

• Coronavirus
• COVID-19
• hACE-2
• MPro
• multi-target-directed ligand
• protease inhibitor
• RdRp
• SARS-CoV-2 virus

Acknowledgments

Authors would like to thank Council of Scientific and Industrial Research (CSIR), New Delhi, India for infrastructure and manpower support. RSJ would like to acknowledge CSIR-National Chemical Laboratory, Pune, India for research start-up grant. SSJ and SBS would like to thankDBT for their research fellowships. SSS acknowledge CSIR for research fellowship and VKP thanks SERB-NPDF (PDF/2017/001544) for fellowship.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The project work is supported by the research grant from the Council of Scientific and Industrial Research (CSIR), New Delhi, India and CSIR-National Chemical Laboratory, Pune, India.