ABSTRACT
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.
Subject(s)
Antiviral Agents , COVID-19 Drug Treatment , Coronavirus 3C Proteases , Ivermectin , Molecular Docking Simulation , Molecular Dynamics Simulation , SARS-CoV-2 , Ivermectin/chemistry , Ivermectin/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/metabolism , Humans , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Protein Binding , Sulfonamides/chemistry , Sulfonamides/pharmacology , Binding Sites , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Lactams , Leucine , Nitriles , ProlineABSTRACT
The potential energy curves (PECs) of all covalent states of Molecular Astatine (At2) have been investigated in this work within a four-component relativistic framework using the MOLFDIR program package. The ground state was determined using multireference configuration interaction with all single and double excitations including Davidson size-extensivity correction (MRCISD+Q) whereas the 22 excited states were treated by complete open shell configuration interaction (COSCI). Spectroscopic constants (Re,ωe,ωexe,ωeye, De,Be,αe,ße,Te) are presented for all states as well as vertical excitations obtained at COSCI, MRCISD and MRCISD+Q levels. In addition, it is also presented accurate extended Rydberg analytical form for the ground state X: (1)0g+.