In Silico Docking of Imidazopyridinyl Acrylonitrile Derivatives to Identify Potential SARS-Cov-2 Inhibitors

The infectious disease caused by COVID-19 was caused by a strain of coronavirus (SARS-CoV-2). It was declared a pandemic in March 2020, leading to 777 millions million cases and 7 millions deaths worldwide. The main protease (MPro) of SARS-CoV-2, a key protease of the virus, mediates viral replication and transcription. SARS-CoV-2 MPro has proven to be an important target for the design and development of drugs against SARS-CoV-2. The aim of this study is to propose a new chemical profile that could be used as an alternative in case of a coronavirus crisis. A literature review revealed that structure-activity relationship studies of MPro protease inhibitors helped identify the key structural features necessary for binding to SARS-CoV-2 MPro through interactions. Based on this, we proposed a series of imidazopyridinyl-acrylonitriles as potential inhibitors of SARS-CoV-2 MPro. Molecular docking studies were conducted on the MPro protein (PDB ID: 5R81) using Schrödinger software. Finally, ADME prediction was used to explore the pharmacokinetic properties. The results of the docking studies showed that imidazopyridinyl acrylonitrile derivatives with a chlorine atom at position 6 showed the best affinities for the target MPro protein (PDB ID: 5R81) and demonstrated favorable ADME characteristics. Furthermore, the trans configuration of the molecules, pi-pi interactions with the nitrogen heterocycle, hydrogen bonding with the pyridinic nitrogen of the imidazopyridine core, and hydrophobic interactions between the chlorine atom and threonine would promote the inhibitory activity of acrylonitrile hybrids on MPro. 6-Chloro-imidazopyridinylacrylonitriles have proven to be promising agents as inhibitors of SARS-CoV-2 MPro, showing significant interactions compared to N-methylpiperazine derivatives.