Antiviral Investigation of Cassia alata L. bioactive compounds for SARS-CoV-2 Mpro: In Silico approach
Dora Dayu Rahma Turista1, Viol Dhea Kharisma2,3, Arif Nur Muhammad Ansori4,5,
Karina Ahmedovna Kardanova6, Islam Ruslanovich Aslanov6,
Ibragim Muhadinovich Dotkulov6, Azret Zamirovich Apshev6, Amir Albertovich Dokshukin6, Maksim Rebezov7,8, Vikash Jakhmola5, Md. Emdad Ullah9, Rahadian Zainul10,11*
1Department of Biology Education, Faculty of Teacher Training and Education,
Mulawarman University, Samarinda, Indonesia.
2Department of Biology, Faculty of Science and Technology, Universitas Airlangga, Surabaya, Indonesia.
3Division of Molecular Biology and Genetics, Generasi Biologi Indonesia Foundation, Gresik, Indonesia.
4Postgraduate School, Universitas Airlangga, Surabaya, Indonesia.
5Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India.
6Medical Faculty, Kabardino-Balkarian State University, Nalchik, Russian Federation.
7Department of Scientific Research, V. M. Gorbatov Federal Research Center for Food Systems,
Moscow, Russian Federation.
8Faculty of Biotechnology and Food Engineering, Ural State Agrarian University,
Yekaterinburg, Russian Federation.
9Department of Chemistry, Mississippi State University, Mississippi, United States.
10Department of Chemistry, Faculty of Mathematics and Natural Sciences,
Universitas Negeri Padang, Padang, Indonesia.
11Center for Advanced Material Processing, Artificial Intelligence, and Biophysic Informatics
(CAMP-BIOTICS), Universitas Negeri Padang, Padang, Indonesia.
*Corresponding Author E-mail: rahadianzmsiphd@fmipa.unp.ac.id
ABSTRACT:
SARS-CoV-2 has caused a prolonged COVID-19 pandemic since the end of December 2019 and is still ongoing now. Bioactive compounds can be used as drugs to treat infectious diseases. This study aims to determine C. alata as a drug candidate for COVID-19 through its inhibitory activity to Mpro SARS-CoV-2 in silico. Cassia alata bioactive compounds have the potential to be used as a candidate for anti-SARS-CoV-2 supported by the result of drug-likeness, ADMET, pharmacokinetics, binding affinity, and antiviral activity prediction. Further research needs to be carried out to make C. alata a drug for COVID-19.
KEYWORDS: SARS-CoV-2, Mpro, Cassia alata, Bioactive compounds.
INTRODUCTION:
The world was shocked by a disease that appeared in Wuhan city, China at the end of December 2019.
The disease has pneumonia symptoms similar to SARS, was named Corona Virus Disease 2019 (COVID-19) in early 2020,1 and was declared a pandemic on March 2020.2
As of 30 November 2022, it has been reported that the virus has infected 638,175,811 people with 6,612,970 mortality.3
COVID-19 is an airborne disease caused by a virus of the genus Betacoronavirus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 name is due to the characteristics of this virus similar to the Sars Corona Virus (SARS-CoV) which causes SARS disease.This virus is+single-strand RNA +(ssRNA)4 and the infection process is mediated by spike glycoprotein (S protein).5 S protein is located on the surface and is the main key in the process of attachment, fusion, and entry of SARS-CoV-2 into the host.6
SARS-CoV-2 encodes a chymotrypsin-like cysteine protease (3CLpro) which is also known as main protease (Mpro).7 Mpro is an enzyme that has a catalytic partner (cysteine and histidine) in its active center.8 Mpro has a key role in the translation process and viral replication. SARS-CoV-2 translate the polyprotein 1 a and 1b(pp1a and pp1ab polypeptides) which are then cleaved by Mpro and one or two papain-like proteases (PLpro) to releasemature 16 non-structural proteins (NSPs) consisting 11 (pp1a) and 5 (pp1ab) that functions for viral replication process so they can proliferate and assemble into new virions.9–12 PLpro and TMPRSS are also critically involved in viral replication, but they are very similar to human enzymes.9 Mpro is present in all types of coronaviruses, indicating a conserved protein that plays a key role in their maturation and other important polyproteins.8 This is why drug discovery is focused on Mpro.
Indonesia is in the tropics and has high plant diversity. Cassia alata L. is one of the wild plants in Indonesia. C. alata leaves contain phytochemicals flavonoids, tannins, saponins, phenolics, and alkaloids.13,14 Furthermore, C. alata contains the bioactive compounds emodin, chrysoeriol, quercetin, kaempferol, and rhein.15 Biological compounds can be used to cure various diseases, both infectious and degenerative diseases.16 Based on the reasons that have been described, this study aims to develop the bioactive compound of C. alata as a drug candidate for anti-SARS-CoV-2 by inhibiting Mpro activity. It is hoped that these findings can also support the WHO Traditional Medicine Strategy program.17
MATERIALS AND METHODS:
Samples preparation:
The bioactive ligand components found in C. alata L. are emodin (CID: 3220), chrysoeriol (CID: 5280666), quercetin (CID: 5280343), kaempferol (CID: 5280863), and rhein (CID: 10168). The 3D ligand structure and Canonical Smile of the compound were downloaded from PubChem (https://pubchem.ncbi.nlm.nih.gov/). The target proteins used were Mpro (PDB ID: 6LU7) downloaded from RCSB PDB (https://www.rcsb.org/). The Mpro sterilization of ligand and water was carried out using AutoDock. The addition of hydrogen on the polar side is done by Auto Dock. Ligand minimization was performedusing PyRx.
Drug-likeness analysis:
The drug-likeness analysis of the C. alata compound is according to Lipinski's rule with four simple physicochemical parameters.18 The bioactive compound of C. alata was analyzed for drug candidate properties using Swiss ADME (http://www.swissadme.ch/index.php) and admetSAR (http://lmmd.ecust.edu.cn/admetsar2/) web server which includes ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity).19,20,21
Antiviral activity prediction:
Antiviral activity predictions are known from the PASS Online web server (http://way2drug.com/PASSOnline/). The standards used are Pa > 0.3 and Pa > Pi. This score is recommended as computational evidence in molecular docking.22
Virtual screening:
Molecular docking was carried out to identify the energy of the binding affinity of C. alata to Mpro. This step was carried out using PyRx software.23 The binding site is determined based on the active site of Mpro when interacting with the N3 inhibitor which is the native ligand.24
Interaction and visualization:
Molecular docking results were visualized using Biovia Discovery Studio 2021. This visualization aims to show the interaction between the phytochemical compounds with Mpro and to determine the binding site pocket.
RESULTS AND DISCUSSION:
Ligand Characteristic:
The prolonged COVID-19 pandemic has sparked the exploration of plant bioactive as anti-SARS-CoV-2.This study used phytochemicals from C. alata as drug candidates for COVID-19.The first step taken was to screen for drug-substance similarities using the Lipinski criteria, this depends on how use the drug.The original RO5 isrelatedto orally active compounds.18RO5 screening results ofC. alatacompounds are shown in Table 1.
Table 1. RO5 of the Cassia alata compounds
|
Compound |
Molecular Formula |
CID |
Molecular Weight (≤500 g/mol) |
logP (≤5) |
H-Bond Donor (≤5) |
H-Bond Acceptor (≤10) |
Meet Ro5 Criteria |
|
Emodin |
C15H10O5 |
3220 |
270.24 |
1.89 |
3 |
5 |
Yes |
|
Chrysoeriol |
C16H12O6 |
5280666 |
300.27 |
2.59 |
3 |
6 |
Yes |
|
Quercetin |
C15H10O7 |
5280343 |
302.24 |
1.99 |
5 |
7 |
Yes |
|
Kaempferol |
C15H10O6 |
5280863 |
286.24 |
2.28 |
4 |
6 |
Yes |
|
Rhein |
C15H8O6 |
10168 |
284.22 |
1.57 |
3 |
5 |
Yes |
Table 2: ADMET of the Cassia alata compounds
|
Compound |
Human Intestinal Absorption |
Plasma Protein Binding |
CYP3A4 Substrat |
CYP3A4 Inhibitor |
Carcinogenety |
|
Emodin |
0.9856 |
100% |
- |
- |
- |
|
Chrysoeriol |
0.9524 |
100% |
+ |
+ |
- |
|
Quercetin |
0.9071 |
100% |
+ |
- |
- |
|
Kaempferol |
0.9499 |
100% |
+ |
+ |
- |
|
Rhein |
0.9866 |
100% |
- |
- |
- |
Screening of likeness drug compounds showed that all selected compounds did not violate the RO5. This indicates that all the selected components of C. alata are safe for oral consumption. The active compound of C. alata is also screened for the pharmacokinetics properties of its drug candidates, which include ADMET. Screening results by using Swiss ADME and admetSAR web server are presented in Table 2.
Compound with Human Immune Absorption (HIA) more than 30% will be labelled +. All C. alata compounds have more than 90% HIA, 100% Protein Plasma Binding, and 100% not carcinogenic.Plasma protein binding (PPB) is critical in modulating the effective drug concentration at pharmacological target sites.25 CYP3A4 one of the main sub-types of cyt P450.26 Cytochrome P450 (cyt P450) is a heme-containing enzyme located in the lipid bilayer of the hepatocyte endoplasmic reticulum membrane.27 C. alata compounds will be easily absorbed by the intestineand have no carcinogenicity.ADMET prediction is very important in drug discovery. Drug candidates with adverse properties tend to fail in clinical trials.28
As a COVID-19 drug candidates, selected compounds from C. alata were also subjected to antiviral activity prediction. The parameters used are antiviral (influenza), antioxidant, free radical scavenger, anti-inflammatory, TNF expression inhibitor, transcription factor NF kappa inhibitor, severe acute respiratory syndrome treatment, transcription factor inhibitor, RNA-directed DNA polymerase inhibitor, and RNA synthesis inhibitor. Screening results via the PASS Online web server are presented in Figure 1.
Figure 1: Relative Score Prediction of Cassia alataAntiviral Activities
The antiviral activity prediction score (Figure 1) reveals that the C. alata component has Pa > Pi and Pa > 0.3404. The acquisition of this value indicates that the active compound contained in C. alata has a higher potential for antiviral activation than its inactivation potential.29 In vitro and in vivo studies are needed to confirm the antiviral activity of these compounds.30
Molecular Docking:
Main protein (Mpro) of SARS-CoV-2 with PDB ID: 6LU7 as a receptor and C. alata compounds (emodin, chrysoeriol, quercetin, kaempferol, andrhein) as ligands. The binding mechanism between macromolecule and small molecules is essential to discover and optimizing drug molecules.31Based on the location of the native ligand, a Gridbox is obtained at the Center X: -14.2030, Y: 11.943, Z: 25.1948 and dimensions X: 17.2539, Y: 20.6596, Z: 25.1948.The position of the binding site on Mprois shown inFigure 2.
Figure 2: Mpro Binding Site
Estimation of the free energy for binding between the C. alata ligand to the active site of the Mpro was carried out through docking analysis.32Docking results show that all ligands are in the same location with the native ligand. Thus, it is hoped that the components of C. alata can compete with essential interactions by interfering with their biological pathways. An effective way to develop Mpro inhibitors is to target the main amino acids of the catalytic site to block their hydrolytic process.33The visualization of ligands on Mpro pocket docking is presented in Figure 3.
Figure 3: Binding Site of All Selected C. alata Compounds with Mpro(PDB ID: 6LU7)
Currently in silico is widely used to develop new antiviral drugs by identifying subsets of compounds in viral proteins.34 Docking analysis serves to identify anti-SARS-Cov-2 ofC. alatacompounds by binding affinity prediction. Molecular docking predicts non-covalent interactions between macromolecules (receptors) and small molecules (ligands) efficiently.31,35,36,37,38 Binding affinity interaction is seen from the free energy that is released. Molecular docking simulation generates several poses with different binding affinity energies.The conformation chosen is based on the lowest binding energy, the results are shown in Figure 4.
Figure 4: The Lowest Binding Affinity of All off Selected C. alata Compounds with Mpro (PDB ID: 6LU7)
Ligands that interact with the receptor will generate affinity energy and the results can be used to determine their binding activity.39 If the binding affinity is negative, it can affect the response activity of the target protein.40 Figure 4 shows that all bioactive compounds of C. alata have inhibitory activity against Mpro, although with different interaction strengths. Kaempferol has the lowest binding affinity value of -7.8, so it has the highest inhibitory activity against Mpro, followed by rhein (-7.5), chrysoeriol (-7.3), quercetin (-7.2), and emodin (-7.2). The lower the binding affinity, the more stable the interaction of the receptor andligand, so the inhibitory activity is also greater. The visualization of the docking complex was carried out using the Biovia Discovery Studio 2021 software. Furthermore, the bonding interactions are explored. The results are shown in Figure 5 and in more detail are presented in Table 3.
Figure 5: Docking Interaction of Mpro (PDB ID: 6LU7) with Cassia alata Compounds
Table 3: Non-bond interaction between Mpro and Cassia alata compounds
|
Compounds |
Binding Affinity (kca/mol) |
Residues in Contact |
Interaction Category |
Distance (Å) |
||
|
|
H-Bond |
Hydrophobic |
Other |
|
||
|
Emodin |
-7,2 |
CYS145 |
ü |
|
|
3,70732 |
|
MET165 |
ü |
|
|
2,98394 |
||
|
HIS41 |
|
ü |
|
5,19387 |
||
|
HIS41 |
|
ü |
|
4,14704 |
||
|
MET165 |
|
ü |
|
4,83514 |
||
|
MET165 |
|
ü |
|
5,36024 |
||
|
Chrysoeriol |
-7,3 |
CYS145 |
|
|
ü |
4,99029 |
|
GLU166 |
ü |
|
|
3,35427 |
||
|
MET165 |
|
|
ü |
5,07587 |
||
|
ASN142 |
ü |
|
|
3,73087 |
||
|
LEU141 |
ü |
|
|
2,28303 |
||
|
SER144 |
ü |
|
|
2,7131 |
||
|
THR190 |
ü |
|
|
2,74308 |
||
|
Quercetin |
-7,2 |
SER144 |
ü |
|
|
3,12554 |
|
SER144 |
ü |
|
|
2,62258 |
||
|
HIS163 |
ü |
|
|
2,24534 |
||
|
ASN142 |
ü |
|
|
2,94743 |
||
|
ARG188 |
ü |
|
|
2,3142 |
||
|
MET165 |
|
|
ü |
5,3224 |
||
|
CYS145 |
|
ü |
|
4,89994 |
||
|
Kaempferol |
-7,8 |
TYR54 |
ü |
|
|
2,51568 |
|
ASP187 |
ü |
|
|
2,16818 |
||
|
GLN189 |
ü |
|
|
2,02291 |
||
|
SER144 |
ü |
|
|
2,28621 |
||
|
GLU166 |
ü |
|
|
3,96573 |
||
|
CYS145 |
|
|
ü |
5,5165 |
||
|
CYS145 |
|
|
ü |
4,94736 |
||
|
MET165 |
|
|
ü |
5,41403 |
||
|
HIS41 |
|
ü |
|
4,81191 |
||
|
MET49 |
|
ü |
|
4,74439 |
||
|
Rhein |
-7,5 |
TYR54 |
ü |
|
|
2,97344 |
|
CYS145 |
ü |
|
|
3,6213 |
||
|
GLU166 |
ü |
|
|
3,36014 |
||
|
ARG188 |
ü |
|
|
3,52529 |
||
|
HIS41 |
|
ü |
|
5,04727 |
||
|
HIS41 |
|
ü |
|
5,62753 |
||
|
CYS145 |
|
ü |
|
5,41853 |
||
|
MET165 |
|
ü |
|
5,1396 |
||
|
CYS145 |
|
ü |
|
5,15813 |
||
There are several types of interactions that stabilize the protein-ligand complex (Figure 5 and Table 3). The SARS-CoV-2 Mpro catalytic pair residue is indicated at HIS41/CYS145.41 Table 3 shows that emodin, kaempferol, and rhein interact with these two residues (HIS41 and CYS145), while chrysoeriol and quercetin do not interact with HIS41. Kaempferol has the lowest binding affinity (-7.8) so it has the most stable interaction. Kaempferol forms the most bonds, namely 10 bonds, consisting of 5 hydrogen bonds, 2 hydrophobic bonds, and 3 other types of bonds which stabilize the interaction between Kaempferol and Mpro. The hydrogen bonds have 2,02291 Å (GLN189) as theclosest distance is and 3,96573 Å (GLU166) as the longest distance. The hydrophobic bond is on HIS41 and MET49 with 4,81191 Å and 4,74439 Å. for other bonds occur in CYS145 (5,5165 Å), CYS145 (4,94736 Å), and MET165 (5,41403 Å) with Pi-Sulfur type interaction.
Hydrogen bonding causes the resulting binding affinity to be more negative so that the bond between the ligand and Mpro becomes more stable. Hydrogen bonds also play a role in optimizing the hydrophobic interactions at the protein-ligand interface so that the binding affinity also increases.42 Hydrogen bonds belong to the group of non-covalent bonds, and non-covalent bonds use much lower energies than covalent interactions.43 The hydrophobic interaction also plays a role in determining the stability of the ligand to Mpro. Hydrophobic interactions are important in drug discovery. This is because hydrophobic bonds can increase the binding affinity between drug-target interfaces.42 Hydrophobic interactions minimize contact with water so that hydrophobic groups form folds into the protein core and provide a significant free energy gain.44,45 Hydrogen and hydrophobic interactions are important in the thermodynamic stability and mechanical properties of Mpro.
Mpro is a key enzyme of the coronavirus and has an important role in mediating viral replication and transcription.46 The bioactive compound of C. alata has the potential to become a Mpro inhibitor, so can prevent the replication and multiplication of SARS-CoV-2. It is hoped that there will be further research to support these findings so that C. alata can be used as a medicinal ingredient to treat COVID-19.
CONCLUSION:
The combination of Cassia alata bioactive compounds has the potential to be used as a candidate for anti-SARS-CoV-2 supported by the result of drug-likeness, ADMET, pharmacokinetics, binding affinity, and antiviral activity prediction. Kaempferol has the lowest binding affinity to Mprothan other compounds. Further research needs to be carried out to make C. alataa drug for COVID-19.
DISCLOSURE STATEMENT:
The authors have no conflicts of interest to declare.
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Received on 18.01.2023 Modified on 04.06.2023
Accepted on 01.10.2023 © RJPT All right reserved
Research J. Pharm. and Tech 2023; 16(12):5610-5616.
DOI: 10.52711/0974-360X.2023.00907