Design of novel viral attachment inhibitors of the spike glycoprotein (S) of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) through virtual screening and dynamics

Abstract To date, the pandemic of COVID-19 causes 11.8 million cases and about 545481 deaths in the world. In this study, we have employed virtual screening approaches and selected 415 lead-like compounds from 103 million chemical substances, based on the existing drugs, from PubChem databases as potential candidates for the S protein-mediated viral attachment inhibition. Thereafter, based on drug-likeness and Lipinski's rules, 44 lead-like compounds were docked within the active side pocket of the viral-host attachment site of the spike protein. Corresponding ligand properties and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile were measured. Furthermore, four novel inhibitors were designed and assessed computationally for its efficacy. From the comparative analysis, we found that our screened compounds maintain better results than the proposed mother compounds VE607 and SSAA09E2. The designed four novel lead compounds possessed more fascinating output without deviating any of the Lipinski's rules. They also showed higher bioavailability and the drug-likeness score of 0.56 and 1.81 respectively compared to the mother compounds. All the screened compounds and novel compounds showed promising ADMET properties. Among them, the compound AMTM-02 was the best candidate through considering comparative analysis with a docking score of -7.5 kcal/mol. Furthermore, the binding study was verified by molecular dynamics simulation over 100ns by assessing the stability of the complex. Thus, we hope that our proposed screened compounds, as well as the novel compounds may give some breakthroughs for the development of a therapeutic drug to treat SARS-CoV-2 proficiently in vitro and in vivo.