In Silico Comparative Analysis of Ivermectin and Nirmatrelvir Inhibitors Interacting with the SARS-CoV-2 Main Protease.

Exploring therapeutic options is crucial in the ongoing COVID-19 pandemic caused by SARS-CoV-2. Nirmatrelvir, which is a potent inhibitor that targets the SARS-CoV-2 Mpro, shows promise as an antiviral treatment. Additionally, Ivermectin, which is a broad-spectrum antiparasitic drug, has demonstrated effectiveness against the virus in laboratory settings. However, its clinical implications are still debated. Using computational methods, such as molecular docking and 100 ns molecular dynamics simulations, we investigated how Nirmatrelvir and Ivermectin interacted with SARS-CoV-2 Mpro(A). Calculations using density functional theory were instrumental in elucidating the behavior of isolated molecules, primarily by analyzing the frontier molecular orbitals. Our analysis revealed distinct binding patterns: Nirmatrelvir formed strong interactions with amino acids, like MET49, MET165, HIS41, HIS163, HIS164, PHE140, CYS145, GLU166, and ASN142, showing stable binding, with a root-mean-square deviation (RMSD) of around 2.0 Å. On the other hand, Ivermectin interacted with THR237, THR239, LEU271, LEU272, and LEU287, displaying an RMSD of 1.87 Å, indicating enduring interactions. Both ligands stabilized Mpro(A), with Ivermectin showing stability and persistent interactions despite forming fewer hydrogen bonds. These findings offer detailed insights into how Nirmatrelvir and Ivermectin bind to the SARS-CoV-2 main protease, providing valuable information for potential therapeutic strategies against COVID-19.

Identification of known drugs as potential SARS-CoV-2 Mpro inhibitors using ligand- and structure-based virtual screening.

Background: The new coronavirus pandemic has had a significant impact worldwide, and therapeutic treatment for this viral infection is being strongly pursued. Efforts have been undertaken by medicinal chemists to discover molecules or known drugs that may be effective in COVID-19 treatment - in particular, targeting the main protease (Mpro) of the virus. Materials & methods: We have employed an innovative strategy - application of ligand- and structure-based virtual screening - using a special compilation of an approved and diverse set of SARS-CoV-2 crystallographic complexes that was recently published. Results and conclusion: We identified seven drugs with different original indications that might act as potential Mpro inhibitors and may be preferable to other drugs that have been repurposed. These drugs will be experimentally tested to confirm their potential Mpro inhibition and thus their effectiveness against COVID-19.