A Review of Bioactive Compounds and Antioxidant Activity Properties of Piper Species.

Antioxidants are compounds that are able to inhibit the negative effects that come from free radicals. The phenomenon of imbalanced antioxidant production and the accumulation of free radicals in cells and tissues can cause oxidative stress. Excessive free radicals that enter the body cannot be warded off by endogenous antioxidant compounds so that the required antioxidant compounds can come from the outside, which helps in the performance of endogenous antioxidants. Antioxidants that come from outside consist of synthetic and natural antioxidants; however, synthetic antioxidants are not an option because they have toxic and carcinogenic effects. Therefore, the use of natural ingredients is an alternative method that is needed to create a new natural antioxidant compound. Piper species are being considered as possible medicinal plants for the development of new sources of antioxidants. Several studies have been carried out starting from the extract levels, fractions, and compounds of the Piper species, which showed good antioxidant activity. Currently, some of these plants are being used as ingredients in traditional medicines to treat allergies, toothaches, and coughs. This review examines the distribution, botanical data, pharmacology, especially antioxidant activity, and the compounds contained in five Piper species, namely Piper amalago L., Piper betle L., Piper hispidum Sw., Piper longum L., and Piper umbellatum L.

In Silico Evaluation of Iranian Medicinal Plant Phytoconstituents as Inhibitors against Main Protease and the Receptor-Binding Domain of SARS-CoV-2.

The novel coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which initially appeared in Wuhan, China, in December 2019. Elderly individuals and those with comorbid conditions may be more vulnerable to this disease. Consequently, several research laboratories continue to focus on developing drugs to treat this infection because this disease has developed into a global pandemic with an extremely limited number of specific treatments available. Natural herbal remedies have long been used to treat illnesses in a variety of cultures. Modern medicine has achieved success due to the effectiveness of traditional medicines, which are derived from medicinal plants. The objective of this study was to determine whether components of natural origin from Iranian medicinal plants have an antiviral effect that can prevent humans from this coronavirus infection using the most reliable molecular docking method; in our case, we focused on the main protease (Mpro) and a receptor-binding domain (RBD). The results of molecular docking showed that among 169 molecules of natural origin from common Iranian medicinal plants, 20 molecules (chelidimerine, rutin, fumariline, catechin gallate, adlumidine, astragalin, somniferine, etc.) can be proposed as inhibitors against this coronavirus based on the binding free energy and type of interactions between these molecules and the studied proteins. Moreover, a molecular dynamics simulation study revealed that the chelidimerine-Mpro and somniferine-RBD complexes were stable for up to 50 ns below 0.5 nm. Our results provide valuable insights into this mechanism, which sheds light on future structure-based designs of high-potency inhibitors for SARS-CoV-2.

In silico Study of Antiviral Activity of Polyphenol Compounds from Ocimum basilicum by Molecular Docking, ADMET, and Drug-Likeness Analysis.

Aim: The SARS-CoV-2 virus is a disease that has mild to severe effects on patients, which can even lead to death. One of the enzymes that act as DNA replication is the main protease, which becomes the main target in the inhibition of the SARS-CoV-2 virus. In finding effective drugs against this virus, Ocimum basilicum is a potential herbal plant because it has been tested to have high phytochemical content and bioactivity. Apigenin-7-glucuronide, dihydrokaempferol-3-glucoside, and aesculetin are polyphenolic compounds found in Ocimum basilicum. Purpose: The purpose of this study was to analyze the mechanism of inhibition of the three polyphenolic compounds in Ocimum basilicum against the main protease and to predict pharmacokinetic activity and the drug-likeness of a compound using the Lipinski Rule of Five. Patients and Methods: The method used is to predict the molecular docking inhibition mechanism using Autodock 4.0 tools and use pkcsm and protox online web server to analyze ADMET and Drug-likeness. Results: The binding affinity for apigenin-7-glucuronide was -8.77 Kcal/mol, dihydrokaempferol-3-glucoside was -8.96 Kcal/mol, and aesculetin was -5.79 Kcal/mol. Then, the inhibition constant values were 375.81 nM, 270.09 nM, and 57.11 µM, respectively. Apigenin-7-glucuronide and dihydrokaempferol-3-glucoside bind to the main protease enzymes on the active sites of CYS145 and HIS41, while aesculetin only binds to the active sites of CYS145. On ADMET analysis, these three compounds met the predicted pharmacokinetic parameters, although there are some specific parameters that must be considered especially for aesculetin compounds. Meanwhile, on drug-likeness analysis, apigenin-7-glucuronide and dihydrokaempferol-3-glucoside compounds have one violation and aesculetin have no violation. Conclusion: Based on the data obtained, Apigenin-7-glucuronide and dihydrokaempferol-3-glucoside are compounds that have more potential to have an antiviral effect on the main protease enzyme than aesculetin. Based on pharmacokinetic parameters and drug-likeness, three compounds can be used as lead compounds for further research.

Appraisal of Bioactive Compounds of Betel Fruit as Antimalarial Agents by Targeting Plasmepsin 1 and 2: A Computational Approach.

In many countries, the fruit of betel (Piper betle Linn) is traditionally used as medicine for treating malaria. It is a fatal disease, and existing medications are rapidly losing potency, necessitating the development of innovative pharmaceutics. The current study attempted to determine the compounds in the n-hexane fraction of betel fruit extract and investigate the potential inhibition of bioactive compounds against aspartic protease plasmepsin 1 (PDB ID: 3QS1) and plasmepsin 2 (PDB ID: 1LEE) of Plasmodium falciparum using a computational approach. The ethanol extract was fractionated into n-hexane and further analyzed using gas chromatography-mass spectrometry (GC-MS) to obtain information regarding the compounds contained in betel fruit. Each compound's potential antimalarial activity was evaluated using AutoDock Vina and compared to artemisinin, an antimalarial drug. Molecular dynamics simulations (MDSs) were performed to evaluate the stability of the interaction between the ligand and receptors. Results detected 20 probable compounds in the n-hexane extract of betel fruit based on GC-MS analysis. The docking study revealed that androstan-17-one,3-ethyl-3-hydroxy-, (5 alpha)- has the highest binding affinity for plasmepsin 1 and plasmepsin 2. The compound exhibits a similar interaction with artemisinin at the active site of the receptors. The compound does not violate Lipinski's rules of five. It belongs to class 5 toxicity with an LD50 of 3000 mg/kg. MDS results showed stable interactions between the compound and the receptors. Our study concluded that androstan-17-one,3-ethyl-3-hydroxy-, (5 alpha)- from betel fruit has the potential to be further investigated as a potential inhibitor of the aspartic protease plasmepsin 1 and plasmepsin 2 of Plasmodium falciparum.

Data on the docking of phytoconstituents of betel plant and matcha green tea on SARS-CoV-2.

Betel (Piper betle L.) and green tea (Camellia sinensis (L) O. Kuntze) have been used for a long time as traditional medicine. The docking of phytoconstituents contained in the betel plant was evaluated against Mpro, and matcha green tea was evaluated against five target receptors of SARS-CoV-2 as follows: spike ectodomain structure (open state), receptor-binding domain (RDB), main protease (Mpro), RNA-dependent RNA polymerase (RdRp), dan papain-like protease (PLpro). The evaluation was carried out based on the value of binding-free energy and the types of interactions of the amino acids at the receptors that interact with the ligands.

Potential of Plant Bioactive Compounds as SARS-CoV-2 Main Protease (Mpro) and Spike (S) Glycoprotein Inhibitors: A Molecular Docking Study.

Since the outbreak of the COVID-19 (coronavirus disease 19) pandemic, researchers have been trying to investigate several active compounds found in plants that have the potential to inhibit the proliferation of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). The present study aimed to evaluate bioactive compounds found in plants using a molecular docking approach to inhibit the main protease (Mpro) and spike (S) glycoprotein of SARS-CoV-2. The evaluation was performed on the docking scores calculated using AutoDock Vina (AV) as a docking engine. A rule of five (Ro5) was calculated to determine whether a compound meets the criteria as an active drug orally in humans. The determination of the docking score was performed by selecting the best conformation of the protein-ligand complex that had the highest affinity (most negative Gibbs' free energy of binding/ΔG). As a comparison, nelfinavir (an antiretroviral drug), chloroquine, and hydroxychloroquine sulfate (antimalarial drugs recommended by the FDA as emergency drugs) were used. The results showed that hesperidin, nabiximols, pectolinarin, epigallocatechin gallate, and rhoifolin had better poses than nelfinavir, chloroquine, and hydroxychloroquine sulfate as spike glycoprotein inhibitors. Hesperidin, rhoifolin, pectolinarin, and nabiximols had about the same pose as nelfinavir but were better than chloroquine and hydroxychloroquine sulfate as Mpro inhibitors. This finding implied that several natural compounds of plants evaluated in this study showed better binding free energy compared to nelfinavir, chloroquine, and hydroxychloroquine sulfate, which so far are recommended in the treatment of COVID-19. From quantum chemical DFT calculations, the ascending order of chemical reactivity of selected compounds was pectolinarin > hesperidin > rhoifolin > morin > epigallocatechin gallate. All isolated compounds' C=O regions are preferable for an electrophilic attack, and O-H regions are suitable for a nucleophilic attack. Furthermore, Homo-Lumo and global descriptor values indicated a satisfactory remarkable profile for the selected compounds. As judged by the RO5 and previous study by others, the compounds kaempferol, herbacetin, eugenol, and 6-shogaol have good oral bioavailability, so they are also seen as promising candidates for the development of drugs to treat infections caused by SARS-CoV-2. The present study identified plant-based compounds that can be further investigated in vitro and in vivo as lead compounds against SARS-CoV-2.