ABSTRACT
The COVID-19 pandemic has accelerated the study of the potential of multi-target drugs (MTDs). The mixture of homologues called ivermectin (avermectin-B1a + avermectin-B1b) has been shown to be a MTD with potential antiviral activity against SARS-CoV-2 in vitro. However, there are few reports on the effect of each homologue on the flexibility and stiffness of proteins associated with COVID-19, described as ivermectin targets. We observed that each homologue was stably bound to the proteins studied and was able to induce detectable changes with Elastic Network Models (ENM). The perturbations induced by each homologue were characteristic of each compound and, in turn, were represented by a disruption of native intramolecular networks (interactions between residues). The homologues were able to slightly modify the conformation and stability of the connection points between the Cα atoms of the residues that make up the structural network of proteins (nodes), compared to free proteins. Each homologue was able to modified differently the distribution of quasi-rigid regions of the proteins, which could theoretically alter their biological activities. These results could provide a biophysical-computational view of the potential MTD mechanism that has been reported for ivermectin.
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.
Subject(s)
Antiviral Agents/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , DNA Helicases/antagonists & inhibitors , Ivermectin/analogs & derivatives , alpha Karyopherins/antagonists & inhibitors , beta Karyopherins/antagonists & inhibitors , Animals , Antiviral Agents/pharmacology , Binding Sites , COVID-19/virology , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , DNA Helicases/chemistry , DNA Helicases/metabolism , Humans , Ivermectin/chemistry , Ivermectin/pharmacology , Kinetics , Mice , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Protein Conformation , Protein Interaction Domains and Motifs , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Thermodynamics , alpha Karyopherins/chemistry , alpha Karyopherins/metabolism , beta Karyopherins/chemistry , beta Karyopherins/metabolism , COVID-19 Drug TreatmentABSTRACT
SARS-CoV-2 has caused millions of infections and more than 600,000 deaths worldwide. Despite the large number of studies to date, there is no specifically effective treatment available for SARS-CoV-2. However, it has been proposed to target reused drugs with potential antiviral activity to the interface between the angiotensin-converting enzymes 2 (ACE2) and the receptor binding domain (RBD) of SARS-CoV-2 to avoid cell recognition. Some non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to have some type of activity against a wide variety of viruses including SARS-CoV-2. Therefore, we carried out an exhaustive computational biophysical study of various NSAIDs targeting the RBD-ACE2 complex using multiple comparative analysis of docking and molecular dynamics. Only the Ibuprofen (Propionic acid derivative), Aspirin (Salicylate), and the Acetaminophen (p-aminophenol derivative) had a thermodynamically favorable docking with the interface of the RBD-ACE2 complex under the conditions of this study. Although, Ibuprofen was the NSAIDs with the most thermodynamically favorable docking in the shortest simulation time, and was the major inducer of structural changes, conformational changes, and overall changes in the complex throughout the simulation, including disturbances in composition and distribution of cavities at the interface. Results that point to Ibuprofen as an NSAID that, under the conditions outlined in this investigation, may have the highest probability of generating a disturbance in the stability of the RBD-ACE2 complex. This statement, although it could contribute information for the empirical treatment and prevention of COVID-19, represents only a theoretical orientation and approach, and requires its experimental demonstration because our predictions cannot secure a pharmacologically and clinically relevant interaction. However, these results are relevant due that suggest a possible mechanism of action of Ibuprofen against COVID-19 in addition to its anti-inflammatory properties, of which there are no reports in the literature. © Copyright © 2020 Gonzalez-Paz, Lossada, Fernández-Materán, Paz, Vera-Villalobos and Alvarado.
ABSTRACT
The pandemic caused by SARS-CoV-2 forces drug research to combat it. Ivermectin, an FDA approved antiparasitic drug formulated as a mixture 80:20 of the equipotent homologous 22,23 dihydro ivermectin (B1_a and B1_b), which is known to inhibit SARS-CoV-2 in vitro with a mechanism of action to be defined. It draws attention powerfully that the energetic and structural perturbation that this drug induces by binding on SARS-COV-2 proteins of importance for its proliferation is ill unknown. Hence what we do an exhaustive computational biophysics study to discriminate the best docking of ivermectins to viral proteins and, subsequently, to analyze possible structural alterations with molecular dynamics. The results suggested that ivermectins are capable of docking to the superficial and internal pocket of the 3CL-protease and the HR2-domain, inducing unfolding/folding that change the native conformation in these proteins. In particular, ivermectin binds to the 3CL protease and leads this protein to an unfolded state, whereas the HR2-domain to a more compact conformation in comparison to the native state by refolding when the drug binding to this protein. The results obtained suggest a possible synergistic inhibitory against SARS-COV-2 owing to each role of ivermectins when favorably binding to these viral proteins. Given the importance of the results obtained about this new mechanism of action of ivermectin on SARS-CoV-2, experimental studies are needed that corroborate this proposal.