26 

In Silico Analysis of Antiviral Activity and Pharmacokinetic 

Prediction of Brazilein Sappan Wood (Caesalpinia sappan L.) 

Against SARS-CoV-2 Spike Glycoproteins  
 

Dwi Krihariyani1, Edy Haryanto1, Retno Sasongkowati1  
 

 
1Department of Medical Laboratory 

Technology, Poltekkes Kemenkes 

Surabaya, Indonesia 

Correspondence: 

Dwi Krihariyani,  

Jl. Wiguna Tengah XIX No.19, 

Surabaya, East Java, Indonesia 

Zip Code: 60294 

 

Email: dwikrihariyani@gmail.com 

 

Received: December 18th, 2020 

Revised: March 20th, 2021 

Accepted: March 22th, 2021 

Published: April 28th, 2021 

 

DOI: 10.33086/ijmlst.v3i1.1854 

 

 

 

 

 

 

 

 

 

 Abstract 

Brazilein is one of the secondary sappan wood metabolites 

which can be used empirically as an antivirus. The SARS-

CoV-2 spike (S) glycoproteins play significant roles in 

attaching and entering the virus into the host cell. This study 

aims to predict the antiviral activity and pharmacokinetic 

properties of brazilein of the sappan wood against the in 

silico SARS-CoV-2 S glycoproteins with vitamin C as the 

reference compound. Molegro Virtual Docker 5.5 was used 

to predict antiviral activity by docking process. SARS-CoV-

2 S glycoprotein with NAG ligand available in Protein Data 

Bank (PDB) (PDB ID: 7C01) was the receptor used. The 

pkCSM online tool was used to predict the pharmacokinetic 

properties and toxicity of brazilein. Data were analyzed on 

the target receptors by comparing the docking bond energies 

between NAG, brazilein, and vitamin C. The smaller the 

ligands’ bond energy to the target receptor, the more stable 

the bonds are. The bond energy of NAG, brazilein, and 

vitamin C was –59.2864 kcal/mol, –65.8911 kcal/mol, and 

–53.9093 kcal/mol, respectively. These results suggested 

that brazilein has a greater capacity as an antivirus compared 

to NAG and vitamin C. In silico test using the pkCSM online 

tool demonstrated that brazilein had strong pharmacokinetic 

properties and relatively low toxicity. 

Keywords 

ADME, Brazilein, NAG, Toxicology, Vitamin C. 
 

  
 

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted 

use, distribution, and reproduction in any medium, provided the original work is properly cited. ©2021 by author. 

 

INTRODUCTION 

In December 2019, mysterious cases of 

pneumonia were first recorded in Wuhan, 

Hubei Province, China (1,2). This disease 

was initially referred to as the 2019 novel 

coronavirus (2019-nCoV). On February 11, 

2020, World Health Organization (WHO) 

declared a new name which was coronavirus 

disease 2019 (COVID-19). The disease was 

caused by severe acute respiratory syndrome 

file:///D:/Users/maharanipertiwikoentjoro/Downloads/dwikrihariyani@gmail.com
https://journal2.unusa.ac.id/index.php/IJMLST/article/view/1854/version/2338


 

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coronavirus 2 (SARS-CoV-2) (3). To date, 

COVID-19 has become a pandemic. 

Coronavirus is one of the significant 

pathogens that can infect the human 

respiratory system and cause mild to severe 

symptoms. Seven coronaviruses are known 

that can infect humans. Four of them (HCoV-

NL63, HCoV-229E, HCoV-OC43, and 

HCoV-HKU1) can infect immunocompetent 

patients with only moderate symptoms. In 

contrast, Middle East Respiratory Syndrome 

Coronavirus (MERS-CoV), Severe Acute 

Respiratory Syndrome Coronavirus (SARS-

CoV), and SARS-CoV-2 cause severe 

symptoms in patients (4,5).  

The pathogenesis of SARS-CoV-2 is still 

unknown, although it is believed not too 

different from that of SARS-CoV. SARS-

CoV-2 mainly infects alveoli-lining airway 

cells (6,7). Host tropism is the key for virus 

infection. If SARS-CoV-2 has identified the 

host cell according to its viral tropism, it will 

bind to the host cell via spike (S) glycoprotein 

(8,9). The S glycoprotein binds to the host 

cell receptor which is the angiotensin-

converting enzyme 2 (ACE2). ACE2 is also 

present in other organs, such as the oral and 

nasal mucosa, nasopharynx, lung, stomach, 

small intestine, large intestine, skin, thymus, 

bone marrow, spleen, liver, kidney, brain, 

pulmonary alveolar epithelial cells, 

enterocyte cells of the small intestine, 

endothelial cells of the venous artery, and 

smooth muscle cells (9,10). Therefore, 

SARS-CoV-2 does not only infect the human 

respiratory system, but also other organs.  

The host cell receptor for SARS-CoV-2 

is the same as SARS-CoV which is ACE2. 

The receptor-binding domain (RBD) 

sequences include the SARS-CoV-2 

receptor-binding motif (RBM) that 

specifically contacts the ACE2. SARS-CoV-

2 RBM interacts with ACE2 in humans with 

residual effects (Gln493), thereby making 

SARS-CoV-2 capable of infecting human 

cells (10,11,12). 

COVID-19 pandemic is a major health 

concern which requires immediate treatment. 

One of the efforts that can be made to combat 

this disease includes enhancing the humans’ 

immune systems. Flavonoids, curcumin, 

limonoids, vitamin C, vitamin E 

(tocopherol), and catechins are good 

candidates which can strengthen the immune 

system (13,14). 

Sappan wood (Caesalpinia sappan L.) 

consists of five flavonoid compounds, 

namely brazilin, brazilein, 3'-O-

methylbrazilin, sappanin, chalcone, and 

sappancalchone. Brazilein is the major 

constituent in sappan wood that is used 

empirically as an antivirus. The five 

compounds can be used as anti-stressants, 

growth promoters, appetite stimulants, 

antiviral drugs, aphrodisiacs, and 

antimicrobial agents (13,15). 

In silico test to determine the potential 

use of brazilein as an antivirus is an attractive 



 

 

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method due to several reasons. This test is 

safe, free of chemical waste, simple, cost-

effective, and can shorten research time 

(16,17). This test is an approach to the 

prediction of chemical properties of 

molecular physics, pharmacokinetic 

properties (absorption, distribution, 

metabolism, and excretion (ADME)), the 

interaction of compounds with receptors, 

mechanisms of action, compound selectivity, 

and compound toxicity.  

Vitamin C, which has been demonstrated 

to have a role in the treatment of COVID-19, 

was used as a reference in this study (18). The 

Protein Data Bank (PDB) 7C01 (molecular 

basis for a potent human neutralizing 

antibody targeting SARS-CoV-2 RBD) was 

used for ligands that have demonstrated good 

biological activities and are able to bind to the 

desired biological target (receptor) of the 

docking. 

Here, we present a study on the 

prediction of the antiviral activity and 

pharmacokinetic properties of brazilein of the 

sappan wood against the in silico SARS-

CoV-2 S glycoprotein with vitamin C as the 

reference compound. 

 

MATERIALS AND METHODS  

The materials included the 3D structures 

of 7C01 which were downloaded from RCSB 

PDB. The 3D structures of 2-acetamido-2-

deoxy-beta-D-glucopyranose (NAG), 

brazilein, and vitamin C were downloaded 

from PubChem®. The tool used in this study 

was a computer with processor 

specifications: Windows 8 64-bit. The 

software used was ChemDraw Professional 

16.0, Chem3D 16.0, and Molegro Virtual 

Docker 5.5. 

Prediction of Operation (Molecular 

Docking) 

ChemDraw Professional 16.0 was used 

to draw the 2D structures of the NAG, 

brazilein, and vitamin C ligands. Chem3D 

16.0 was then used to convert them to 3D 

structures. This software was also used to 

find the most stable conformation. After the 

minimum energy of NAG, brazilein, and 

vitamin C ligands were calculated, 

{SYBYL2 (*. Mol2)} was stored in the 

format of mol2. The results were in the form 

of rerank score (RS), which was the energy 

needed in the process of ligand-receptor 

interaction. From this score, the antiviral 

activity of brazilein can be predicted.  

Physicochemical, pharmacokinetic, and 

toxicity prediction of compounds 

(pkCSM) 

The pkCSM online method has been used 

to predict physicochemical properties, such 

as the molecular weight (MW), octanol/water 

partition coefficient logarithm (Log P), the 

number of bonds between atoms that can 

rotate (torsion), hydrogen bond acceptors 

(HBA), hydrogen bond donors (HBD), and 

polar surface area (PSA). In this study, the 

pkCSM online tool was used to predict the 



 

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pharmacokinetic properties and toxicity of 

NAG, brazilein and vitamin C. Firstly, the 2D 

molecular structures of NAG, brazilein, and 

vitamin C were drawn with the ChemDraw 

Professional 16.0 program. Secondly, they 

were copied to the Chem3D 16.0 program to 

be converted into 3D structures (saved as 

*.sdf files). Thirdly, online SMILES 

Translator was used to transform the 

structures of NAG, brazilein, and vitamin C 

into SMILES format. Compounds are 

subsequently processed in SMILES format 

using the pkCSM online tool to predict the 

ADME and toxicity. Protox online tool 

(http://tox.charite.de/tox/) was used to 

predict the oral toxicity (LD50) in the 

Globally Harmonized System (GSH) (17,19). 

  

RESULTS 

Prediction of Operation (Molecular 

Docking) 

The 2D structures of NAG, brazilein, and 

vitamin C are depicted in Figure 1, whereas 

the 3D structures of NAG, brazilein, and 

vitamin C are depicted in Figure 2.

  

 
(a) 

 

 
(b) 

 

  
 

(c) 

Figure 1. 2D structures. (a) NAG, (b) brazilein, (c) and vitamin C  

(ChemDraw Professional 16.0) 

 

 

   

(a) (b) (c) 

Figure 2. 3D structures. (a) NAG, (b) brazilein, (c) and vitamin C (Chem3D 16.0) 

 

 

 

http://tox.charite.de/tox/


 

 

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Prediction of Docking and Amino Acid  

The protein structures of PDB 7C01 are 

depicted in Figure 3, whilst the interaction 

between the ligands (NAG, brazilein, and 

vitamin C) and receptors on the 7C01 protein 

is depicted in Figure 4. 

Figure 5 and Table 1 indicate the amino 

acids involved in the interactions of NAG, 

brazilein, and vitamin C compounds with the 

7C01 protein receptor. Table 2 displays the 

redocking effects of NAG, brazilein, and 

vitamin C with 7C01 protein receptor. 

 

 
Figure 3. Protein structures (PDB 7C01) (Molegro Virtual Docker 5.5) 

 

   

Figure 4. Receptor interactions between the ligands of  

(a) NAG, (b) brazilein, (c) and vitamin C (Molegro Virtual Docker 5.5) 

 

   

Figure 5. Amino acids involved in the interactions of (a) NAG, (b) brazilein, (c) and vitamin 

C (c) with 7C01 protein receptor (H-bond, electrostatic, and steric)  

(Molegro Virtual Docker 5.5) 

a b c 

a b c 



 

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Table 1. Amino acids involved in the interactions of NAG (a), brazilein (b), and vitamin C (c) 

with 7C01 protein receptor (H-bond, electrostatic, and steric). 

Ligands 

Hydrogen bonds 

and amino acid 

residues 

Electrostatic 

interactions and amino 

acid residues 

Steric interactions 

and amino acid 

residues 

NAG 0 – 0 – 1 Asn 343(A) 

Brazilein 1 Asn 343(A) 0 – 2 
Asn 343(A) 

Leu 368(A) 

Vitamin C 1 Asn 343(A) 0 – 1 Asn 343(A) 

 

Table 2. Redocking results using the Molegro Virtual Docker 5.5. 

Redocking/Ligand NAG Brazilein Vitamin C 

I –51.5568 –58.0565 –45.9314 

II –59.2864 –65.8911 –53.9093 

III –51.2831 –55.7692 –46.8643 

 

Physicochemical, pharmacokinetic, and 

toxicity prediction of compounds 

(pkCSM) 

The results of the in silico predictions for 

physicochemical parameters of NAG, 

brazilein, and vitamin C are presented in 

Table 3. 

The in silico predictions of 

pharmacokinetic properties and toxicity of 

NAG, brazilein, and vitamin C are presented 

in Table 4. 

 

Table 3. In silico predictions for physicochemical parameters of NAG, brazilein, and vitamin C. 

Struktur 

SMILES 

NAG Brazilein 
 

Vitamin C 

MW 221.209 284.267 176.124 

Log P –3.0776 1.624 –1.4074 

Torsion 2 0 2 

HBA 6 5 6 

HBD 5 3 4 

PSA (A2) 86.290 119.652 67.321 

MW = molecular weight; log P = logarithm of the octanol/water partition coefficient; torsion = bonds between atoms 

that can rotate; HBA = hydrogen bond acceptors; HBD = hydrogen bond donors; PSA = polar surface area. 

 



 

 

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Table 4. In silico predictions of pharmacokinetic properties and toxicity of NAG, brazilein, and 

vitamin C. 

Pharmacokinetic properties and toxicity NAG Brazilein 
Vitamin 

C 

Intestinal absorption (human) (%) 19.518 90.021 39.716 

Skin permeability (log Kp) –3.264 –3.498 –3.198 

Vss (human) (log L/kg) –0.101 0.194 –0.156 

BBB permeability (log BB) –1.023 –0.662 –1.031 

CYP2D6 substrate (Yes/No) No No No 

CYP2D6 inhibitior (Yes/No) No No No 

Total Clearance (log ml/min/kg) 0.718 0.264 0.631 

OCT2 substrate (Yes/No) No No No 

Ames toxicity (Yes/No) No Yes No 

 LD50 (mol/kg) 1.714 2.246 1.271 

Vss: steady-state volume of distribution; BBB: blood-brain barrier; CYP2D6: cytochrome P2D6; OCT2: organic 

cation transporter 2. 

 

 

DISCUSSION 

Activity Prediction (Molecular Docking) 

In this study, SARS-CoV-2 S 

glycoprotein with NAG_601[A] ligand (PDB 

7C01) was the target molecular receptor. 

PDB 7C01 was selected since it is 

homologous with SARS-CoV-2 S 

glycoprotein. The host cell receptor for 

SARS-CoV-2 is the same as SARS-CoV 

which is ACE2. The RBD sequence involves 

SARS-CoV-2 RBM in direct contact with the 

ACE2 (20). NAG_601[A] ligand was 

selected since it demonstrated good 

biological activity and can bind to the desired 

biological target during the docking process 

to determine the molecules’ physical and 

chemical properties. The functional groups of 

NAG, brazilein, and vitamin C responsible 

for pharmacophores which can reduce 

activity, as well as the lipophilic, 

electrostatic, and steric/geometric properties 

of the functional groups, were searched using 

Molegro Virtual Docker 5.5. This was 

conducted in order to design the minimum 

structural characteristics needed for further 

medicine production development (21). 

Physical and chemical properties (e.g. 

lipophilic and electrostatic properties) of the 

drugs play an essential role in transporting 

the drugs to reach the virus (i.e. absorption 

and delivery). Only drugs that have a high 

specificity structure can interact and cause 

activity with the biological receptors. 

Furthermore, the drugs’ electrostatic and 

steric properties play a role in promoting the 

precise orientation of the receptor surface 

molecule (21). 



 

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Docking and Amino Acid Analysis Activity 

Prediction 

The protein receptor (PDB 7C01) that 

was downloaded and imported into the 

Molegro Virtual Docker 5.5 is presented in 

Figure 3. Figure 4 depicts the detection 

results of the interaction between the three 

ligands and S glycoprotein. Cavity (volume 

2587.14) with active NAG_601[A] ligand 

was used because there is a region where the 

NAG ligand interacts with the S 

glycoprotein. 

There was a ligand interaction with 

multiple amino acid residues from the 7C01 

protein receptor in the interaction between 

the ligands and receptors. Figure 5 and Table 

1 indicate the amino acids involved in the 

NAG, brazilein, and vitamin C interaction 

pathway with the 7C01 protein receptor. The 

lipophilic/hydrophobic bond, electronic, and 

steric interactions of the amino acid residues 

of the protein receptor with these compounds 

take place. There were variations in the 

interactions with the S glycoprotein receptor 

between each of the NAG, brazilein, and 

vitamin C compounds (Figure 5 and Table 1) 

since there were differences in the spatial 

arrangement of the three compound 

structures. 

The effects of redocking with the 7C01 

protein receptor for NAG, brazilein, and 

vitamin C are displayed in Table 2. The 

binding energy of brazilein with the 7C01 

protein receptor was lower than NAG and 

vitamin C ligands. Brazil had a RS of                           

–65,8911 kcal/mol, whereas NAG and 

vitamin C had RSs of –59,2864 kcal/mol and 

–53,9093 kcal/mol, respectively. It indicated 

that brazilein supplied lower energy than 

NAG and vitamin C, hence binding to the 

receptor would be more stable compared to 

NAG and vitamin C. 

 

Physicochemical, pharmacokinetic, and 

toxicity prediction of compounds 

(pkCSM) 

The results of the in silico prediction of 

NAG, brazilein, and vitamin C 

physicochemical parameter values are 

displayed in Table 3. Lipinski et al. (1997) 

analyzed 2,245 drugs from the baseline 

World Drugs Index and concluded that if the 

molecular weight is greater than 500 Da, the 

compounds would be difficult to be absorbed, 

have low permeability, have a log value of +5 

octanol/water (log P) partition coefficient, 

have HBD expressed by the number of 

groups O-H and N-H greater than 5, and have 

an H-bond. Since all values are the 

multiplication of five, this analysis is known 

as Lipinski's Rule of Five (20). It can be 

analyzed from Table 3 that NAG, brazilein, 

and vitamin C had molecular weight of less 

than 500 Da, logP values of less than 5, 

acceptor and donor values of less than 10, 

hence it can be inferred that it is easy to 

absorb these three compounds. 



 

 

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The in silico pharmacokinetic properties 

and toxicity predictions of NAG, brazilein, 

and vitamin C are presented in Table 4. 

According to Chander et al. (21), a compound 

is categorized as having strong absorption 

capacity if the absorption value is > 80%, 

whereas it has poor absorption capacity if the 

absorption value is < 30%. The primary site 

for absorption of oral medications is the 

intestine (22). Table 4 shows that NAG’s 

human intestinal absorption value was less 

than 30%, whereas brazilein’s and vitamin 

C’s were more than 80%. These results 

suggested that brazilein and vitamin C had 

better absorption capacity than NAG. 

Pires et al. (20) stated that a compound is 

described to have relatively low skin 

permeability if its value is log Kp > –2.5 (23). 

Table 4 displays that the skin permeability 

(log Kp) of NAG, brazilein, and vitamin C 

was lower than –2.5, hence these three 

compounds were supposed to have strong 

skin permeability.   

The volume of distribution (Vd) refers to 

the theoretical volume that is required to 

distribute the total dose of the medicine 

equally in order to give the same 

concentration as in the blood plasma. The 

higher the Vd value, the more drugs than 

blood plasma are distributed to the body’s 

tissues. Pires et al. (20) stated that a 

compound is described to have high Vd if the 

value of log Vd is > 0.45, but low Vd if the 

value of log Vd is < –0.15 (19). The steady-

state volume of distribution (Vss) values for 

NAG, brazilein, and vitamin C were –0.101, 

0.194, and –0.156 (Table 4), thus it could be 

estimated that all the derivatives of these 

compounds can be uniformly distributed to 

have the same concentration as in blood 

plasma. 

Another significant parameter to 

consider is the ability of drugs to cross the 

blood-brain barrier (BBB) to help decrease 

side effects and toxicity, or to improve the 

effectiveness of drugs whose 

pharmacological activity is present in the 

brain. BBB permeability is calculated as log 

BB (the logarithmic ratio of brain-to-plasma 

concentrations) in vivo in an animal model. 

Pires et al. (20) stated that compounds are 

believed to be able to pass the BBB 

effectively if their log BB values are > 0.3, 

and cannot be adequately distributed if their 

log BB values are < –1 (23). The log BB 

values of NAG, brazilein, and vitamin C were 

–1.023, –0.662, and –1.031, respectively 

(Table 4). The log BB value of brazilein was 

higher than –1, while NAG’s and vitamin C’s 

were lower than –1, hence it was expected 

that brazilein was capable of penetrating the 

BBB moderately, while NAG and vitamin C 

compounds were less capable. 

Most of the metabolic reactions require 

oxidation process. Cytochrome P450 is an 

essential detoxification enzyme in the body, 

and it is primarily found in the liver. 

Cytochrome P450 acts by oxidizing and 



 

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promoting the excretion of unidentified 

organic compounds, including narcotics. 

Enzyme inhibitors, such as grapefruit juice, 

are contraindicated against cytochrome P450 

enzymes since it can affect drug metabolism. 

It is therefore important to assess the ability 

of compounds to inhibit cytochrome P450, 

which is represented as the cytochrome P2D6 

(CYP2D6) isoform in this study. Table 4 

displays that the CYP2D6 enzyme is not 

impaired or inhibited by NAG, brazilein, and 

vitamin C, thus it could be expected that these 

derivatives appear to be metabolized by the 

P450 enzyme (19). 

The compound excretion process can be 

carried out by calculating the total clearance 

(CLtot) and renal organic cation transporter 2 

(OCT2) substrate constants. CLtot is a 

mixture of liver clearance (liver and bile 

metabolism) and renal clearance (excretion 

through the kidneys). This is related to 

bioavailability. To achieve steady-state 

concentrations, it is necessary to determine 

the dosage level (19). CLtot values of NAG, 

brazilein, and vitamin C were 0.718, 0.264, 

and 0.631, respectively (Table 4). Therefore, 

the rate of compound excretion could be 

estimated from these values.  

OCT2 is a kidney-based transporter that 

plays a significant role in drug and 

endogenous compound disposal and 

clearance. When given along with OCT2 

inhibitors, OCT2 substrates also have the 

potential to cause side interactions. The three 

compounds did not affect the OCT2 

substrates (Table 4), thus it could be 

interpreted that the NAG, brazilein, and 

vitamin C derivatives were not substrates of 

OCT2. 

To assess the toxicity of the compounds, 

the Ames toxicity test was carried out. The 

Ames Toxicity Test is a commonly used 

method to determine the mutagenic ability of 

bacteria-based compounds. A positive test 

result indicates the mutagenicity of the 

compound and may thus serve as a 

carcinogen (19). Brazilein might cause 

mutagenic effects, while NAG and vitamin C 

were not expected to cause mutagenic effects 

(Table 4). 

 

CONCLUSIONS 

The bond energy of brazilein was lower 

than NAG and vitamin C. The comparison of 

the bond energy values showed that brazilein 

had higher antiviral capacity than NAG and 

vitamin C in silico using the molecular 

docking process. The physicochemical, 

pharmacokinetic, and toxicity properties of 

brazilein showed that it was projected to have 

strong skin permeability, be distributed 

uniformly to provide the same concentration 

as in the blood plasma, be penetrating the 

BBB moderately, be very well absorbed in 

the intestine, be metabolized by the P450 

enzyme, and have relatively low toxicity. 

 

 



 

 

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AUTHOR CONTRIBUTIONS 

Dwi Krihariyani: conceptualization, 

software, formal analysis, writing the original 

draft, and visualization. Edy Haryanto: 

methodology, validation, writing, review, 

and editing. Retno Sasongkowati: 

supervision, writing, review, and editing. 

 

 

ACKNOWLEDGMENT 

Utmost gratitude was given to Prof. Dr. 

Siswandono, Apt., M.S. from Faculty of 

Pharmacy, Universitas Airlangga (Surabaya, 

Indonesia) who gave the authors the Molegro 

Virtual Docker license 5.5. 

 

CONFLICT OF INTEREST 

None to declare. 

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