(R)-(+)-Rosmarinic Acid as an Inhibitor of Herpes and Dengue Virus Replication: an In Silico Assessment

Abstract

Since ancient times, viruses such as dengue, herpes, Ebola, AIDS, influenza, chicken meat, and SARS have been roaming around causing great health burdens. Currently, the prescribed antiviral drugs have not cured the complications caused by viruses, whereas viral replication was not controlled by them. The treatments suggested are not only ineffectual, but also sometimes inefficient against viruses at all stages of the viral cycle as well. To fight against these contagious viruses, people rely heavily on medicinal plants to enhance their innate and adaptive immune systems. In this research, the preparation of ligands and proteins was performed using the Maestro V.13.2 module tool. This software, consisting of LigPrep, Grid Generation, SiteMap, and Glide XP, has each contributed significantly to the preparation of ligands and proteins. Ultimately, the research found that (R)-(+)-rosmarinic acid was found to have significant docking scores of - 10.847 for herpes virus, of - 10.033 for NS5, and - 7.259 for NS1. In addition, the Prediction of Activity Spectra for Substances (PASS) server indicates that rosmarinic acid possesses a diverse spectrum of enzymatic activities, as probability active (Pa) values start at > 0.751, whereas it has fewer adverse effects than the drugs prescribed for viruses. Accordingly, it was found the rate of acute toxicity values of (R)-(+)-rosmarinic acid at doses LD₅₀ log10 (mmol/g) and LD₅₀ (mg/g) in different routes of administration, such as intraperitoneal, intravenous, oral, and subcutaneous. Ultimately, the present study concluded that (R)-(+)-rosmarinic acid would expose significant antiviral effects in in vitro and in vivo experiments, and this research would be a valuable asset for the future, especially for those who wish to discover a drug molecule for a variety of viruses.

Supplementary information: The online version contains supplementary material available at 10.1007/s43450-023-00381-y.

Keywords: Acute toxicity; Antiviral drug; Biomedical profile; MM-GBSA; Pharmacophore.

Fig. 1

Route of viral infections and their genomes: A when a mosquito carrying the dengue virus bites a person, the virus penetrates the skin along with the mosquito’s saliva. It binds to and enters white blood cells and reproduces in the cells as they move through the body, producing several signaling proteins such as cytokines and interferons that are responsible for many of the symptoms, such as fever, flu-like symptoms, and severe pain. Once in the skin, the virus enters cells by binding between viral proteins and membrane proteins on the Langerhans cell, specifically the C-type lectins. One of the first things required for viral DNA to replicate is the suppression of the host’s cellular protein synthesis. B HSV infection occurs by binding to cells through rampant receptors that reflect a variety of host tissue infections, including sensory neurons, which leads to latency. Nuclear and cytoplasmic stages of virus replication also occur (created in BioRender.com)

Fig. 2

Docking of (R)-(+)-rosmarinic acid (1) to the 1F5Q murine gamma herpesvirus cyclin complexed to human cyclin-dependent kinase 2. a Residues and hydrogen bond contacts with their distance values among the ligand and catalytic pocket amino acids of the 1F5Q protein. b Revealed interactions between the hydroxy and oxygen groups of (R)-(+)-rosmarinic acid with 1F5Q

Fig. 3

Docking of (R)-(+)-rosmarinic acid (1) to the 2J7W dengue virus NS5 RNA-dependent RNA polymerase domain complexed with 3' dGTP. a Residues and hydrogen bond contacts with their distance values among the ligand and catalytic pocket amino acids of the 2J7W protein. b Revealed interactions between the hydroxy and oxygen groups of (R)-(+)-rosmarinic acid with 2J7W

Fig. 4

Docking of (R)-(+)-rosmarinic acid (1) to the 4OIG dengue virus dengue virus nonstructural protein NS1. a Residues and hydrogen bond contacts with their distance values among the ligand and catalytic pocket amino acids of the 4OIG protein. b Revealed interactions between the hydroxy and oxygen groups of (R)-(+)-rosmarinic acid with 4OIG

Fig. 5

Pharmacophore hypothesis of (R)-(+)-rosmarinic acid (1). A denotes hydrogen bond acceptor in pink color, D denotes hydrogen bond donor in blue. and R denotes aromatic rings in brown color from docked phytochemicals; A–D showed the active site of docked phytochemicals developed by e-Pharmacophore

Fig. 6

Acute toxicity for (R)-(+)-rosmarinic acid (1) at different routes of administration at LD50 dose (predicted by Gusar). Abbreviations: i.p., intraperitoneal; i.v., intravenous; s.c., subcutaneous administration