Screening of Clinically Approved and Investigation Drugs as Potential Inhibitors of SARS-CoV-2 Main Protease and Spike Receptor-Binding Domain Bound with ACE2 COVID19 Target Proteins: A Virtual Drug Repurposing Study

Serdar Durdagi, Busecan Aksoydan, Berna Dogan, Kader Sahin, Aida Shahraki, Necla Birgül-İyison

10.26434/chemrxiv.12032712.v2

Research curated

Abstract

In this virtual drug repurposing study, we used 7922 FDA approved drugs and compounds in clinical investigation from NPC database. Both apo and holo forms of SARS-CoV-2 Main Protease as well as Spike Protein/ACE2 were used for virtual screening. Initially, docking was performed for these compounds at target binding sites. The compounds were then sorted according to their docking scores which represent binding energies. The first 100 compounds from each docking simulations were initially subjected to short (10 ns) MD simulations (in total 300 ligand-bound complexes), and average binding energies during MD simulations were calculated using the MM/GBSA method. Then, the selected promising hit compounds based on average MM/GBSA scores were used in long (100-ns and 500-ns) MD simulations. In total around 15 µs MD simulations were performed in this study. Both docking and MD simulations binding free energy calculations showed that holo form of the target protein is more appropriate choice for virtual drug screening studies. These numerical calculations have shown that the following 8 compounds can be considered as SARS-CoV-2 Main Protease inhibitors: Pimelautide, Rotigaptide, Telinavir, Ritonavir, Pinokalant, Terlakiren, Cefotiam and Cefpiramide. In addition, following 5 compounds were identified as potential SARS-CoV-2 ACE-2/Spike protein domain inhibitors: Denopamine, Bometolol, Naminterol, Rotigaptide and Benzquercin. These compounds can be clinically tested and if the simulation results validated, they may be considered to be used as treatment for COVID-19.

Source: ChemRxiv

Related molecules

Name	Synonyms	Genes
Pinokalant
Terlakiren
Cefotiam
Denopamine
Bometolol
Naminterol
Rotigaptide
Telinavir
Pimelautide
Angiotensin-converting enzyme 2-Spike glycoprotein interface
Benzquercin
3C-like protease	3CLpro, Mpro, SARS coronavirus main peptidase, 3CLpro-SARS-CoV-2	rep, ORF1a-1b
Cefpiramide
Ritonavir

Related interactions

Target	Drug	Type	Result
3C-like protease	Pimelautide	Computational	positive
3C-like protease	Rotigaptide	Computational	positive
3C-like protease	Telinavir	Computational	positive
3C-like protease	Pinokalant	Computational	positive
3C-like protease	Terlakiren	Computational	positive
3C-like protease	Cefotiam	Computational	positive
3C-like protease	Cefpiramide	Computational	positive
Angiotensin-converting enzyme 2-Spike glycoprotein interface	Denopamine	Computational	positive
Angiotensin-converting enzyme 2-Spike glycoprotein interface	Bometolol	Computational	positive
Angiotensin-converting enzyme 2-Spike glycoprotein interface	Naminterol	Computational	positive
Angiotensin-converting enzyme 2-Spike glycoprotein interface	Benzquercin	Computational	positive
Angiotensin-converting enzyme 2-Spike glycoprotein interface	Rotigaptide	Computational	positive
3C-like protease	Ritonavir	Computational	positive