In Silico Analysis of Antiviral Activity and Pharmacokinetic Prediction of Brazilein Sappan Wood (Caesalpinia sappan L.) Against SARS-CoV-2 Spike Glycoproteins

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 SARSCoV-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-CoV2 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.

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 angiotensinconverting 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.

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.

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     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.

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  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.  (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.

34
The in silico pharmacokinetic properties and toxicity predictions of NAG, brazilein, and vitamin C are presented in Table 4.  (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).