Theoretical and experimental study of interaction of macroheterocyclic compounds with ORF3a of SARS-CoV-2

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.

Viroporins: Structure, function, and their role in the life cycle of SARS-CoV-2

“…Electrophysiological data on heterologously expressed 3a protein in Xenopus oocytes revealed inhibition of 3a induced currents by Kaempferol derivatives ( Schwarz, Sauter et al 2014 ) and Emodin ( Schwarz, Wang et al 2011 ). A molecular docking study on 23 compounds and subsequent experimental testing using fluorescence and UV-Vis spectroscopy identified chlorin, iron(III) protoporphyrin and protoporphyrin as a putative binding partners of ORF 3a ( Lebedeva, Gubarev et al 2021 ). In a drug repurposing approach, bacteria-based functional assays that measured growth retardation, K + uptake, and change of cytoplasmic pH of E. coli that overexpressed the 3a protein of SARS-CoV-2 were tested ( Tomar, Krugliak et al 2021 ).…”

Main Strategies for the Synthesis of meso-Arylporphyrins

“…Nowadays, of particular importance is the use of tetrapyrrole macroheterocycles for biomedical pur­poses. Apart from the well-established efficiency of porphyrin-based photodynamic therapy agents [ 6 – 17 ], the ability of these compounds to inactivate various viruses, including SARS-CoV-2, opens prospects of creating new alternative approaches to the treatment of drug-resistant viral and bacterial infections [ 18 – 20 ].…”

Cheminformatics-Based Discovery of Potential Chemical Probe Inhibitors of Omicron Spike Protein

“…Furthermore, modified extracellular vesicles (EVs) fused with palmitoylated ACE2 (PM-ACE2-EV) demonstrated the neutralization potency against authentic SARS-CoV-2 both in vitro and in vivo [ 29 ]. Various antiviral drugs and possible potential treatments using experimental and theoretical techniques are also being examined against Omicron and other SARS-CoV-2 variants [ 30 , 31 , 32 , 33 , 34 ]. Takashita and co-authors investigated the reactivity of three antiviral drugs (Remdesivir, Molnupiravir, and PF-07304814) and the seven monoclonal antibodies by means of enzyme-linked immunosorbent assay (ELISA) coated with recombinant Spike protein derived from the Wuhan strain, and other variants including, Alpha, Beta, Gamma, Delta, and Omicron variants.…”