ABSTRACT
The treatment of coronavirus COVID-19, like other viral diseases, is currently underdeveloped. This fact necessitates the search for new drugs and treatment methods that will effectively disrupt the life cycle of the virus. A big problem in the therapy of viral diseases is the ability of viruses to evade the host's immune response. We suppose that the search for drugs that can change the evasiveness of the virus from the immune response of the host is a very promising strategy, as it can help the body to cope with the infection. Protein SARS-CoV-2 ORF8 is one of the key proteins that can suppress antiviral immunity. This paper considers the available information on the structure and functioning of ORF8, as well as the results of molecular docking of ORF8 to a wide range of tetrapyrrole macroheterocyclic compounds capable of generating reactive oxygen species upon photoirradiation. This principle of photoinactivation of biosubstrates underlies the methods of photodynamic therapy of cancer. Application of photoinactivation of drug-resistant forms of bacteria and some viruses can be useful in the fight against COVID-19 and other viral infections. In this work, the structure of ORF8 complexes with macrocyclic compounds is considered in detail, the dependence of their binding affinity on the nature of macrocycles and the nature of peripheral substituents is analyzed and spectral studies of the binding of ORF8 to chlorin is performed. This paper is a part of a large project to investigate the possibility of using macrocyclic compounds for the treatment of viral diseases.Communicated by Ramaswamy H. Sarma.
ABSTRACT
The pandemic infectious disease (Covid-19) caused by the coronavirus (SARS-CoV2) is spreading rapidly around the world. Covid-19 does an irreparable harm to the health and life of people. It also has a negative financial impact on the economies of most countries of the world. In this regard, the issue of creating drugs aimed at combating this disease is especially acute. In this work, molecular docking was used to study the docking of 23 compounds with QRF3a SARS-CoV2. The performed in silico modeling made it possible to identify leading compounds capable of exerting a potential inhibitory and virucidal effect. The leading compounds include chlorin (a drug used in PDT), iron(III)protoporphyrin (endogenous porphyrin), and tetraanthraquinone porphyrazine (an exogenous substance). Having taken into consideration the localization of ligands in the QRF3a SARS-CoV2, we have made an assumption about their influence on the pathogenesis of Covid-19. The interaction of chlorin, iron(III)protoporphyrin and protoporphyrin with the viral protein ORF3a were studied by fluorescence and UV-Vis spectroscopy. The obtained experimental results confirm the data of molecular docking. The results showed that a viral protein binds to endogenous porphyrins and chlorins, moreover, chlorin is a competitive ligand for endogenous porphyrins. Chlorin should be considered as a promising drug for repurposing.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/metabolism , Heterocyclic Compounds/chemistry , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/metabolism , Viroporin Proteins/chemistry , Viroporin Proteins/metabolism , Binding Sites , Drug Repositioning , Heterocyclic Compounds/metabolism , Ligands , Molecular Docking Simulation , Porphyrins/chemistry , Porphyrins/metabolism , Protoporphyrins/chemistry , Protoporphyrins/metabolism , SARS-CoV-2/drug effects , Viroporin Proteins/antagonists & inhibitors , COVID-19 Drug TreatmentABSTRACT
In this work, we analyze the latest data on the molecular docking of a range of SARS-CoV-2 proteins to protoporphyrin IX, verteporfin, and chlorin e6, as well as consider the prospects for using chlorins and porphyrins as agents for photoinactivation of the SARS2 virus.