Exploring Niclosamide as a Multi-target Drug Against SARS-CoV-2: Molecular Dynamics Simulation Studies on Host and Viral Proteins

Niclosamide has emerged as a promising repurposed drug against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In vitro studies suggested that niclosamide inhibits the host transmembrane protein 16F (hTMEM16F), crucial for lipid scramblase activity, which consequently reduces syncytia formation that aids viral spread. Based on other in vitro reports, niclosamide may also target viral proteases such as papain-like protease (PLpro) and main protease (Mpro), essential for viral replication and maturation. However, the precise interactions by which niclosamide interacts with these multiple targets remain largely unclear. Docking and molecular dynamics (MD) simulation studies were undertaken based on a homology model of the hTMEM16F and available crystal structures of SARS-CoV-2 PLpro and Mpro. Niclosamide was observed to bind stably throughout a 400 ns MD simulation at the extracellular exit gate of the hTMEM16F tunnel, forming crucial interactions with residues spanning the TM1-TM2 loop (Gln350), TM3 (Phe481), and TM5-TM6 loop (Lys573, Glu594, and Asp596). Among the SARS-CoV-2 proteases, niclosamide was found to interact effectively with conserved active site residues of PLpro (Tyr268), exhibiting better stability in comparison to the control inhibitor, GRL0617. In conclusion, our in silico analyses support niclosamide as a multi-targeted drug inhibiting viral and host proteins involved in SARS-CoV-2 infections.