Identification of potential Mpro inhibitors for the treatment of COVID-19 by using systematic virtual screening approach

• Published in: Molecular diversity Vol. 25; no. 1; pp. 383 - 401
• Main Authors: Kanhed, Ashish M., Patel, Dushyant V., Teli, Divya M., Patel, Nirav R., Chhabria, Mahesh T., Yadav, Mange Ram
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.02.2021; Springer Nature B.V
• Subjects: Antiviral Agents - therapeutic use; Biochemistry; Biomedical and Life Sciences; Coronavirus 3C Proteases - antagonists & inhibitors; Coronaviruses; COVID-19; COVID-19 - virology; COVID-19 Drug Treatment; Drug development; Drug Evaluation, Preclinical - methods; Humans; Libraries; Life Sciences; Mass Screening - methods; Molecular Docking Simulation; Organic Chemistry; Original; Original Article; Pandemics - prevention & control; Pharmacy; Polymer Sciences; Protease Inhibitors - pharmacology; SARS-CoV-2 - drug effects; SARS-CoV-2 - metabolism; Severe acute respiratory syndrome coronavirus 2; Viral Nonstructural Proteins - antagonists & inhibitors; COVID-19; Virtual screening; Asinex BioDesign; Coronavirus; Mpro; Severe acute respiratory syndrome
• ISSN: 1381-1991; 1573-501X
• DOI: 10.1007/s11030-020-10130-1

The Co rona vi rus D isease (COVID-19) is caused because of novel coronavirus (SARS-CoV-2) pathogen detected in China for the first time, and from there it spread across the globe creating a worldwide pandemic of severe respiratory complications. The virus requires structural and non-structural proteins for its multiplication that are produced from polyproteins obtained by translation of its genomic RNA. These polyproteins are converted into structural and non-structural proteins mainly by the main protease (Mpro). A systematic screening of a drug library (having drugs and diagnostic agents which are approved by FDA or other world authorities) and the Asinex BioDesign library was carried out using pharmacophore and sequential conformational precision level filters using the Schrodinger Suite. From the screening of approved drug library, three antiviral agents ritonavir, nelfinavir and saquinavir were predicted to be the most potent Mpro inhibitors. Apart from these pralmorelin, iodixanol and iotrolan were also identified from the systematic screening. As iodixanol and iotrolan carry some limitations, structural modifications in them could lead to stable and safer antiviral agents. Screenings of Asinex BioDesign library resulted in 20 molecules exhibiting promising interactions with the target protein Mpro. They can broadly be categorized into four classes based on the nature of the scaffold, viz. disubstituted pyrazoles, cyclic amides, pyrrolidine-based compounds and miscellaneous derivatives. These could be used as potential molecules or hits for further drug development to obtain clinically useful therapeutic agents for the treatment of COVID-19. Graphic abstract