Destabilizing the structural integrity of COVID-19 by caulerpin and its derivatives along with some antiviral drugs: An in silico approaches for a combination therapy

Abstract

Presently, the SARS-CoV-2 (COVID-19) pandemic has been spreading throughout the world. Some drugs such as lopinavir, simeprevir, hydroxychloroquine, chloroquine, and amprenavir have been recommended for COVID-19 treatment by some researchers, but these drugs were not effective enough against this virus. This study based on in silico approaches was aimed to increase the anti-COVID-19 activities of these drugs by using caulerpin and its derivatives as an adjunct drug against SARS-CoV-2 receptor proteins: the SARS-CoV-2 main protease and the SARS-CoV-2 spike protein. Caulerpin exhibited antiviral activities against chikungunya virus and herpes simplex virus type 1. Caulerpin and some of its derivatives showed inhibitory activity against Alzheimer’s disease. The web server ANCHOR revealed higher protein stability for the two receptors with disordered score (< 0.6). Molecular docking analysis showed that the binding energies of most of the caulerpin derivatives were higher than all the suggested drugs for the two receptors. Also, we deduced that inserting NH 2 , halogen, and vinyl groups can increase the binding affinity of caulerpin toward 6VYB and 6LU7, while inserting an alkyl group decreases the binding affinity of caulerpin toward 6VYB and 6LU7. So, we can modify the inhibitory effect of caulerpin against 6VYB and 6LU7 by inserting NH 2 , halogen, and vinyl groups. Based on the protein disordered results, the SARS-CoV-2 main protease and SARS-CoV-2 spike protein domain are highly stable proteins, so it is quite difficult to unstabilize their integrity by using individual drugs. Also, molecular dynamics (MD) simulation indicates that binding of the combination therapy of simeprevir and the candidate studied compounds to the receptors was stable and had no major effect on the flexibility of the protein throughout the simulations and provided a suitable basis for our study. So, this study suggested that caulerpin and its derivatives could be used as a combination therapy along with lopinavir, simeprevir, hydroxychloroquine, chloroquine, and amprenavir for disrupting the stability of SARS-CoV2 receptor proteins to increase the antiviral activity of these drugs.

Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2 in Vitro

“…The copyright holder for this this version posted December 2, 2020. ; https://doi.org/10.1101/2020.12.02.408112 doi: bioRxiv preprint binding of different HCV PI to SARS-CoV-2 M pro . [48][49][50][51][52][53][54][55][56][57][58][59][60][62][63][64][65][66][67][68]74 In several of these studies HCV PI were identified as top candidates following screening of large drug libraries, however, some of these studies also yielded contradictory results. Of these studies, 10 identified simeprevir 50,53,58,60,62,63,[65][66][67][68] , 5 paritaprevir 49,53,55,63,66 , 3 glecaprevir [54][55][56] , telaprevir 48,53,64 , boceprevir 48,57,59 and faldaprevir 48,60,…”

“…48–60,62–68,74 In several of these studies HCV PI were identified as top candidates following screening of large drug libraries, however, some of these studies also yielded contradictory results. Of these studies, 10 identified simeprevir 50,53,58,60,62,63,65–68 , 5 paritaprevir 49,53,55,63,66 , 3 glecaprevir 54–56 , telaprevir 48,53,64 , boceprevir 48,57,59 and faldaprevir 48,60,74 , 2 danoprevir 48,51 and asunaprevir 48,60 and 1 sovaprevir 48 , vaniprevir 48 , narlaparevir 48 and grazoprevir 52 to bind M pro . Recently, 4 groups reported studies of HCV PI voxilaprevir, boceprevir and simeprevir in cell-based antiviral assays.…”

Combination and tricombination therapy to destabilize the structural integrity of COVID-19 by some bioactive compounds with antiviral drugs: insights from molecular docking study

“…The docking validation was carried out using our previously published work [36] with re-docking of the co-crystal structure (N3) as an inhibitor in the 6LU7 with the abovementioned parameters and values in the "Materials and methods" section. Firstly, N3 coordinates in the crystal complex of 6LU7 were removed and the bond orders were checked.…”

“…Canscora decussata [35] Sargassum naozhouense [33] Antioxidant and a cell protective effect on a monkey kidney fibroblast cell line, [36] and anticancer, antibacterial, and antifungal activities [37] Hexadecanoic acid (8) Terrestrial plant Canthium parviflorum [38] Antimicrobial, anti-inflammatory, antioxidant, hypocholesterolemia, pesticide, hemolytic and 5-alpha reductase inhibitor [40] and antiviral activity [41] Caulerpin (10) Green macroalgae Red macroalgae…”

Secondary Metabolites from Caulerpa Cylindracea (Sonder) Could Be Alternative Natural Antiviral Compounds for COVID-19: A Further in Silico Proof

“…Some in-silico studies have shown that some natural bioactive compounds including caulerpin (CPN) have inhibitory properties for the Mpro [12]. Same research group published a subsequent report to show the inhibitory properties of CPN and its derivatives on the Mpro and S-Protein of SARS-CoV-2 [13]. In this study, we wanted to study further by using Blind docking technology developed by UCAM-HPC and also propose another important secondary metabolite caulerpenyne (CYN) of C.cylindracea.…”