Comparative study of the interaction of ivermectin with proteins of interest associated with SARS-CoV-2: A computational and biophysical approach

Abstract

The SARS-CoV-2 pandemic has accelerated the study of existing drugs. The mixture of homologs called ivermectin (avermectin-B1a [HB1a] + avermectin-B1b [HB1b]) has shown antiviral activity against SARS-CoV-2 in vitro . However, there are few reports on the behavior of each homolog. We investigated the interaction of each homolog with promising targets of interest associated with SARS-CoV-2 infection from a biophysical and computational-chemistry perspective using docking and molecular dynamics. We observed a differential behavior for each homolog, with an affinity of HB1b for viral structures, and of HB1a for host structures considered. The induced disturbances were differential and influenced by the hydrophobicity of each homolog and of the binding pockets. We present the first comparative analysis of the potential theoretical inhibitory effect of both avermectins on biomolecules associated with COVID-19, and suggest that ivermectin through its homologs, has a multiobjective behavior.

Comparative study of SARS-CoV-2 infection in different cell types: Biophysical-computational approach to the role of potential receptors

“…In the sampling of the probabilistically most feasible and thermodynamically most favorable positions in the complexes, only the three runs with the most favorable berth were considered. This criterion was used to discriminate the complexes that would be subjected to further analysis, including molecular dynamics [ 23 ].…”

“…Molecular dynamics (MD) simulations for favorable docking were performed with two purposes: 1) to study the relative stability of the bond; and 2) obtain the minimum energy conformation of the complexes. For a protein-protein complex, the MD system was first relaxed through a series of minimization procedures that include three phases: relaxation, equilibrium, and sampling, as recommended [ 23 ]. The MD simulation of the crystalline structures was carried out in an explicit water system.…”

“…For calculations of mean squared deviations (RMSD), the equation, where δ i is the distance between atom i and a reference structure or the average position of the n equivalent atoms. All MD simulations and additional adjustments were performed using COSGENE/myPresto [ 23 , 26 ]. Additionally, to predict conformational changes in each protein-protein complexes after its interaction, the NMSim software ( https://cpclab.uni-duesseldorf.de/nmsim/main.php ) was used, which is a computational technique that uses a three-step including coarse-graining (CG), normal mode analysis (NMA), and elastic network model (ENM) to provide realistic conformations in reasonable computation times.…”

“…The ROG-guided NMSim simulation is a method to search for a conformation of a given protein-protein complex, allowing to describe the compactness of a protein. In an ROG-guided NMSim simulation, the trajectory is tailored towards the bound structure by selecting the pathway that leads to a decrease in Radius of gyration (Rg), and conformations are generated by structure distortion along directions of random linear combinations of low-frequency normal modes [ 23 ].…”

Interaction of the new inhibitor paxlovid (PF-07321332) and ivermectin with the monomer of the main protease SARS-CoV-2: A volumetric study based on molecular dynamics, elastic networks, classical thermodynamics and SPT

“…The crystal structure of the main protease of SARS-CoV-2 (PDB: 6LU7) was used as it is a key enzyme of coronaviruses and has a fundamental role in mediating viral replication and translation, making it an attractive target for drugs ( González-Paz et al, 2021 , González-Paz et al, 2021 ). All structures were obtained in PDB format from the RCSB Protein Data Bank ( https://www.rcsb.org/ ).…”