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Chikodili, I.M., Chioma, I.I., Ukamaka, I.A., Nnenna, O.T., Ogechukwu, O.D., Mmesoma, E., Chikodi, E.C., IfedibaluChukwu, E.I. Phytocompound inhibitors of caspase 3 as beta-cell apoptosis treatment development option: An In-silico approach. Sciences of Phytochemistry 2023, 2(1), 17-37.
Chikodili, IM, Chioma, II, Ukamaka, IA, Nnenna, OT, Ogechukwu, OD, Mmesoma, E, Chikodi, EC, IfedibaluChukwu, EI. Phytocompound inhibitors of caspase 3 as beta-cell apoptosis treatment development option: An In-silico approach. Sciences of Phytochemistry. 2023; 2(1):17-37.
Igbokwe Mariagoretti Chikodili, Ibe Ifeoma Chioma, Ilechukwu Augusta Ukamaka, Oju Theclar Nnenna, Okoye Delphine Ogechukwu, Ernest Eze Mmesoma, Ekeomodi Christabel Chikodi, Ejiofor InnocentMary IfedibaluChukwu. 2023. "Phytocompound inhibitors of caspase 3 as beta-cell apoptosis treatment development option: An In-silico approach" Sciences of Phytochemistry 2, no. 1:17-37.
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Home / Sciences of Phytochemistry / Volume 2 Issue 1 / 10.58920/sciphy02010017
Research Article
by Igbokwe Mariagoretti Chikodili, Ibe Ifeoma Chioma, Ilechukwu Augusta Ukamaka, Oju Theclar Nnenna, Okoye Delphine Ogechukwu, Ernest Eze Mmesoma, Ekeomodi Christabel Chikodi, Ejiofor InnocentMary IfedibaluChukwu ★
Academic editor: James H. Zothantluanga
Sciences of Phytochemistry 2(1): 17-37 (2023); https://doi.org/10.58920/sciphy02010017
This article is licensed under the Creative Commons Attribution (CC BY) 4.0 International License.
Abstract: The prevalence of Diabetes mellitus (DM) is continuously rising worldwide. Among its types, type I is characterized by the destruction of beta cells triggered by various mechanisms, including the activation of Caspase 3. Studies have demonstrated the crucial role of Caspase 3 in initiating the apoptosis of beta cells in DM. Our research aims to identify possible phytocompounds inhibitors of Caspase 3 using computational approach. We obtained 3D structures of Caspase 3 and 6511 phytocompounds from the Protein Data Bank and the African Natural Products Database, respectively. The phytocompounds were assessed for druglikeness properties, topological polar surface area, and preliminary toxicity using DataWarrior. The phytocompounds were subjected to molecular docking simulation (MDS) at Caspase 3 active site using AutoDock-Vina. The frontrunner phytocompounds obtained from the MDS were subjected to protease inhibition prediction on Molinspiration. The pharmacokinetics of the phytocompounds were assessed on SwissADME. The in-depth computational toxicity profile of the phytocompounds was evaluated on the pkCSM web. The binding interactions of the phytocompounds with Caspase 3 were assessed with Discovery Studio Visualizer and Maestro. Seventeen phytocompounds were found to have no violation of Lipinski's rule and had no toxicity based on the preliminary assessment, have better binding affinity and protease inhibitory prediction scores than the references, have optimistic bioactivity radar prediction and similar amino acids interaction, in comparison with the references. Further studies, which include in-vitro and in-vivo studies, will be carried out to validate the results of this study.
Keywords: Diabetesbeta-cellsapoptosisCaspase 3phytocompoundsin-silico
Beta-cell apoptosis is a critical event in
the pathogenesis of type 1 diabetes mellitus (DM). Aside from being the primary
mechanism by which cells are destroyed, beta-cell apoptosis has been linked to
the onset of type 1 DM via antigen cross-presentation mechanisms that result in
beta-cell-specific T-cell activation (1). Apoptosis can be activated via the
extrinsic death receptor or intrinsic mitochondrial pathway, activating
effector caspases (2). Apoptosis is also a critical process in the development
of atherosclerosis (2).
Caspases are endoproteases and genes
crucial for preserving homeostasis by controlling cell death and inflammation.
A phylogenetically conserved death program that is essential for the
homeostasis and growth of higher organisms carefully regulates their
activation. Numerous human diseases are primarily pathogenetic due to the
dysregulation of apoptosis. Caspases are potential therapeutic targets because
they are part of the apoptotic machinery (3, 4).
Caspases are classified broadly according
to their known roles in apoptosis (caspase-3, -6, -7, -8, and -9 in mammals)
and inflammation (caspase-1, -4, -5, -12 in humans and caspase-1, -11, and -12
in mice). Caspase-2, -10, and -14 functions are more difficult to classify.
Caspases involved in apoptosis have been divided into two groups based on their
mechanism of action: initiator caspases (caspases - 8 and -9) and executioner
caspases (caspase-3, -6, and -7) (3).
In a study titled "Caspase-3-Dependent
-Cell Apoptosis in the Initiation of Autoimmune Diabetes Mellitus", the
authors used a genetic approach to show that this process is necessary for
cross-presentation of beta-cell antigen to activate beta-cell-specific T cells (1).
They proved that mice lacking caspase-3 do not experience the onset of
autoimmune diabetes, which is indicated by normal level of glucose
concentration in the blood, unaffected beta-cells revealing high insulin
content, and absence of beta-cell specific T-cell activation in the pancreatic
draining lymph nodes. In a different study titled "Immunocytochemical
localization of caspase-3 in pancreatic islets from type 2 diabetic
subjects", the author reported finding more cleaved caspase-3
immunostained islets from type 2 diabetics, which may indicate an accelerated
apoptotic cascade in the islets, along with increasing amyloid deposition
before ultimate cell death (5).
The improper control of caspase-mediated
cell death and inflammation is linked to various illnesses, including
inflammatory, neurological, and other metabolic diseases and cancer. It may be
necessary to therapeutically target caspase-3 activity in cells to stop the
onset of autoimmune diabetes (1). Numerous natural and synthetic caspase
inhibitors have been discovered and created to be used therapeutically. Only a
few synthetic caspase inhibitors have progressed into clinical trials due to
their lacklustre efficacy or harmful side effects. They have yet to prove
compelling enough for patient use (6).
The aim of this study is to detect
phytocompounds with drug like properties in African plants that could inhibit
Caspase-3 through in-silico analysis.
The materials used are personal computer,
African Natural Compounds Database, PubChem (http://Pubchem.ncbi.nlm.nih.gov) (7),
Linux operating system (Ubuntu desktop 18.04), Protein data bank
(https://www.rcsb.org/) (8), DataWarrior software (9), PyMOL software (10),
AutoDockTools-1.5.6 software (11), AutoDock Vina 1.1.2 software (12), on Ubuntu
operating system, and Molinspiration Chemoinformatics web tool
(https://www.molinspiration.com/cgi-bin/properties) (13).
To find essential targets and receptors for
apoptotic processes, literatures were explored. This was done to examine the
role of the target and receptors in the pathophysiology and initiation of cell
apoptosis. This provides more details regarding the receptor's characteristics,
activities, and druggability.
Caspase 3 in 3D
format was retrieved from Protein Data Bank (PDB) with the PDB ID: 3KJF after
various targets and receptors had been identified, literature had been mined,
and the target and receptor had been analyzed. PyMOL program was initially used
to prepare the pdb file by selecting the necessary chains and deleting multiple
ligands. To understand how the ligands attach to receptors, PyMOL software was
used. The AutoDockTools was used to get the receptor ready for molecular
docking simulations. The receptors were prepared by adding polar hydrogens and
Kollman's charges before storing them in the pdbqt file format, the structural
format needed for performing molecular docking simulation on Autodock vina. As
shown in Table 1, the electrostatic grid boxes and the three-dimensional
affinity with various sizes and centers were formed around the protein's active
region.
Table 1. Grid box parameters used for
the molecular docking simulations
|
3KJF |
|
Centres |
Sizes |
|
X |
21.94 |
14 |
Y |
-4.306 |
14 |
Z |
10.718 |
14 |
In this study, 6511 phytocompounds were
examined, which were obtained from the African Natural Products Database
(African-compounds.org) (14, 15). The compounds were downloaded as 3D-structure
data files for analysis. Various parameters such as partition coefficient (Log
P), topological polar surface area (TPSA), molecular weight, hydrogen bond
donor, and hydrogen bond acceptor were used to assess the phytocompounds. Some
of the phytocompounds were found to infringe Lipinski's rule. Those that did
not breach the rule underwent toxicological assessment for mutagenicity, carcinogenicity,
tumorigenicity, and reproductive effect.
Phytocompounds with no Lipinski’s rule of
five infarction and no predicted toxicity (mutagenicity, carcinogenicity,
tumorigenicity, and reproductive effect) in-silico
were prepared for the molecular docking simulation. Reference ligands were
identified from the literature, including the compound co-crystallized with the
receptor/protein on the PDB database. In preparation for the ligands for
molecular docking simulation, all rotatable bonds, torsions, and Gasteiger
charges were assigned and saved in the pdbqt file format.
The PDB structure of the 3KJF (Caspase 3)
protein, in association with a reference inhibitor as was downloaded from the PDB,
was replicated in-silico to validate
the molecular docking simulations procedure for this protein. Other known
inhibitors of Caspase 3 were also used for the validation, including
Flubendazole, Fenoprofen, Pranoprofen, and Diflunisal (16). The
AutoDockTools-1.5.6 was used to calculate polar hydrogen, Kollman charges, grid
box sizes, and centers at a grid space of 1.0 (11, 12). The protein was stored
as a pdbqt file. AutoDockTools-1.5.6 was used to prepare the reference
chemicals for molecular docking simulation. Torsion-free bonds, as well as any
other rotatable bonds, were permitted. After that, files with the pdbqt
extension were generated as output. On a Linux environment, a virtual screening
shell script was used to locally implement the AutoDockVina® molecular docking
simulation of the protein and reference chemical utilizing the centers and
sizes (12). Co-crystal inhibitor binding interaction was compared with the
re-docked co-crystalized compounds, Flubendazole, Fenoprofen, Pranoprofen, and
Diflunisal using PyMol-1.4.1 software and Discovery studio visualizer.
The phytocompounds were prepared in batches
for molecular docking simulations using virtual screening scripts against the
Caspase 3. Following the validation of docking methods, four replicates of
Molecular Docking Simulations were performed on a Linux platform using
AutoDockVina® and related tools. To determine the leading phytocompounds,
binding free energy values (kcal/mol SD) were ranked.
The online Molinspiration web tool version
2011.06 (www.molinspiration.com) was supplied SMILES notations of the leading
phytocompounds to forecast the bioactivity scores for protease inhibition.
The top phytocompounds underwent a thorough
pharmacokinetics evaluation using SwissADME, a web-based tool that assesses the
druglikeness, physicochemical, ADME properties, and medicinal chemistry compatibility
of small molecules (17). The assessment was conducted to examine the
pharmacokinetics of the lead phytocompounds in detail.
An in-depth toxicity prediction of the
frontrunner phytocompounds for AMES toxicity, Max. tolerated dose (human), hERG
I inhibitor, hERG II inhibitor, Oral Rat Acute Toxicity (LD50), Oral
Rat Chronic Toxicity (LOAEL), Hepatotoxicity, Skin Sensitization, T. Pyriformis toxicity and Minnow
toxicity on the pkCSM platform (18).
The amino acids of Caspase 3 binding
interactions with each frontrunner phytocompounds were analyzed using Discovery
Studio Visualizer v20.1.0.19295, and Maestro 13.3 aided the generation of 2D
structures of the interaction for easy observation (19, 20).
The drug-likeness assessment of the 6511 phytocompounds was performed using Lipinski's rule of five to screen out phytocompounds that violated the guidelines on the DataWarrior application. Following the screening, 3814 phytocompounds had no infraction of Lipinski's rule, but 2697 phytocompounds did. Toxicity testing on the 3814 phytocompounds that did not violate Lipinski's criteria was performed using DataWarrior to discover phytocompounds that could be mutagenic, tumorigenic, irritating, or have reproductive implications. In-silico testing revealed that 1897 phytocompounds possessed none of the identified toxicities. The total polar surface area (TPSA) was also calculated for each phytocompounds.
The docking procedure
was validated to assure the in-silico
repeatability of the experimental protein-ligand interactions gathered from the
protein data bank and to observe Caspase 3 amino-acids-conventional hydrogen
bond interactions with the reference compounds known as inhibitors of caspase
3. Table 2 shows the binding energy of the docked co-crystalized ligand and that
of the reference known inhibitors of caspase 3. Figure 2 is the 2D
representation of the docked co-crystalized ligand and reference compounds with
the specific Caspase 3 amino acids involved in the interaction. Table 3 shows
each reference compound, docked co-crystalized ligand, and the docked
co-crystalized ligand with the specific amino acids involved in their
interaction with caspase 3.
Table 2. Mean binding energies
of the docked co-crystalized ligand and reference compounds
No. |
Reference compounds |
Mean Binding Affinity |
Standard Deviation |
1 |
Flubendazole |
-7.60 |
0.20 |
2 |
Diflunisal |
-7.20 |
0.00 |
3 |
B92 (Co-crystalized) |
-7.13 |
0.15 |
4 |
Pranoprofen |
-6.50 |
0.00 |
5 |
Fenoprofen |
-6.18 |
0.05 |
Figure 1. 2D representations of the docked co-crystalized ligand and
reference compounds amino acids interaction
Table 3. Mean binding energies
of the docked co-crystalized ligand and reference compounds
No. |
Reference compounds |
Amino
acids |
1 |
B92 |
ARG 207,SER 205, SER 209 |
2 |
B92 (Co-crystalized) |
ARG 207, SER 209, PHE 250 |
3 |
Diflunisal |
ASN 208, SER 209 |
4 |
Pranoprofen |
ASN 208 |
5 |
Fenoprofen |
SER 209 |
6 |
Flubendazole |
ARG 207, ASN 208, PHE 250 |
To identify
phytocompounds with greater in silico binding energies against Caspase 3
than the co-crystalized ligand and reference compounds, molecular docking
of the phytocompounds was carried out on Caspase 3. The result is presented in
table 4, showing
phytocompounds with higher mean binding energies than the co-crystalized
ligand and reference
compounds. The table also contains Lipinski's rule parameters and TPSA values of
the phytocompounds.
Table 4. Phytocompounds
with better mean binding affinities than the reference compounds
No. |
Compound name |
Mean Binding Affinity |
Standard Deviation (±) |
Molecular Weight |
Octanol-Water Coefficient |
Hydrogen Bond Acceptors |
Hydrogen Donor |
Topological Polar Surface Area |
1 |
Amataine |
-9.20 |
0.00 |
493.65 |
-2.75 |
7.00 |
2.00 |
49.04 |
2 |
3'-epi-afroside |
-9.20 |
0.00 |
534.64 |
1.07 |
9.00 |
4.00 |
134.91 |
3 |
Neoilexonol |
-8.70 |
0.00 |
442.73 |
6.67 |
2.00 |
1.00 |
37.30 |
4 |
Chrysophanol-10,10'-bianthrone |
-8.70 |
0.00 |
478.50 |
4.70 |
6.00 |
4.00 |
115.06 |
5 |
Hydroxyhopane |
-8.50 |
0.00 |
426.73 |
7.16 |
1.00 |
1.00 |
20.23 |
6 |
Taraxast-20-ene-3beta,30-diol |
-8.50 |
0.00 |
446.76 |
8.49 |
2.00 |
2.00 |
40.46 |
7 |
Caulindole
A |
-8.50 |
0.00 |
368.52 |
5.38 |
2.00 |
2.00 |
31.58 |
8 |
Acacic
acid lactone |
-8.50 |
0.00 |
470.69 |
4.79 |
4.00 |
2.00 |
66.76 |
9 |
3-oxo-12beta-hydroxy- Oleanan-28,13beta-olide |
-8.50 |
0.00 |
430.67 |
5.60 |
3.00 |
1.00 |
46.53 |
10 |
Lucidene |
-8.50 |
0.00 |
416.60 |
8.00 |
2.00 |
0.00 |
18.46 |
11 |
Millettone |
-8.40 |
0.00 |
382.41 |
1.24 |
6.00 |
0.00 |
77.05 |
12 |
Taraxasterol |
-8.30 |
0.00 |
424.71 |
7.00 |
1.00 |
1.00 |
20.23 |
13 |
5,6-dehydrocalotropin |
-8.30 |
0.00 |
532.63 |
0.79 |
9.00 |
3.00 |
131.75 |
14 |
Chrysophanol-
isophyscion Bianthrone |
-8.30 |
0.00 |
508.53 |
4.63 |
7.00 |
4.00 |
124.29 |
15 |
Uguenensene |
-8.30 |
0.00 |
484.59 |
2.99 |
7.00 |
0.00 |
87.50 |
16 |
Calotroproceryl
acetate A |
-8.10 |
0.00 |
466.75 |
7.74 |
2.00 |
0.00 |
26.30 |
17 |
Lupeol |
-8.10 |
0.00 |
440.75 |
7.98 |
1.00 |
1.00 |
20.23 |
18 |
Beta-amyrin |
-8.10 |
0.00 |
426.73 |
7.34 |
1.00 |
1.00 |
20.23 |
19 |
Anastatin
B |
-8.10 |
0.00 |
378.34 |
3.58 |
7.00 |
4.00 |
120.36 |
20 |
3-hydroxycycloart-24-one |
-8.10 |
0.00 |
442.73 |
6.86 |
2.00 |
1.00 |
37.30 |
21 |
Diketo
leucolactone |
-8.10 |
0.00 |
468.68 |
5.04 |
4.00 |
1.00 |
63.60 |
22 |
Sigmoidin
E |
-8.08 |
0.22 |
406.48 |
5.55 |
5.00 |
2.00 |
75.99 |
23 |
Di-podocarpanoid
hugonone A |
-8.08 |
0.25 |
586.85 |
4.53 |
6.00 |
5.00 |
118.22 |
24 |
24-methylene
cycloartanol |
-8.05 |
0.06 |
440.75 |
8.34 |
1.00 |
1.00 |
20.23 |
25 |
Isojamaicin |
-8.05 |
0.06 |
378.38 |
3.73 |
6.00 |
0.00 |
63.22 |
26 |
Seneganolide |
-8.03 |
0.05 |
470.52 |
1.37 |
8.00 |
1.00 |
112.27 |
27 |
24-methylencycloartanol |
-8.00 |
0.00 |
438.74 |
8.08 |
1.00 |
1.00 |
20.23 |
28 |
Scalarolide |
-8.00 |
0.00 |
386.57 |
4.51 |
3.00 |
1.00 |
46.53 |
29 |
Citriquinochroman |
-8.00 |
0.00 |
442.47 |
3.88 |
7.00 |
2.00 |
89.79 |
30 |
Matricolone |
-8.00 |
0.00 |
286.41 |
3.36 |
2.00 |
1.00 |
37.30 |
31 |
Epi-lupeol |
-8.00 |
0.00 |
426.73 |
7.65 |
1.00 |
1.00 |
20.23 |
32 |
20-epi-isoiguesterinol |
-8.00 |
0.00 |
424.62 |
5.19 |
3.00 |
2.00 |
57.53 |
33 |
Melliferone |
-8.00 |
0.00 |
452.68 |
5.64 |
3.00 |
0.00 |
43.37 |
34 |
Abyssinone
I |
-8.00 |
0.00 |
322.36 |
3.87 |
4.00 |
1.00 |
55.76 |
35 |
Argeloside
O |
-7.93 |
0.05 |
521.63 |
0.31 |
9.00 |
0.00 |
112.58 |
36 |
Calotropursenyl
acetate B |
-7.90 |
0.00 |
468.76 |
7.84 |
2.00 |
0.00 |
26.30 |
37 |
Beta-anhydroepidigitoxigenin |
-7.90 |
0.00 |
356.50 |
3.47 |
3.00 |
1.00 |
46.53 |
38 |
3-acetyltaraxasterol |
-7.90 |
0.00 |
468.76 |
7.84 |
2.00 |
0.00 |
26.30 |
39 |
Lupeol
acetate |
-7.90 |
0.00 |
480.77 |
8.20 |
2.00 |
0.00 |
26.30 |
40 |
Siphonellinol
C |
-7.90 |
0.00 |
490.72 |
5.04 |
5.00 |
4.00 |
90.15 |
41 |
Isoadiantol |
-7.90 |
0.00 |
426.73 |
7.11 |
1.00 |
1.00 |
20.23 |
42 |
3-acetylsesterstatin
1 |
-7.90 |
0.00 |
446.63 |
4.07 |
5.00 |
1.00 |
72.83 |
43 |
1,5-di-O-caffeoylquinic
acid |
-7.90 |
0.00 |
426.73 |
7.59 |
1.00 |
0.00 |
17.07 |
44 |
Tingenin
B |
-7.90 |
0.00 |
438.61 |
4.55 |
4.00 |
2.00 |
74.60 |
45 |
Friedelane-3,7-dione |
-7.90 |
0.00 |
440.71 |
6.88 |
2.00 |
0.00 |
34.14 |
46 |
Norisojamicin |
-7.90 |
0.00 |
364.35 |
3.46 |
6.00 |
1.00 |
74.22 |
47 |
A-homo-3a-oxa-5beta- Olean-12-en-3-
one-28-oic acid |
-7.90 |
0.00 |
471.70 |
3.58 |
4.00 |
0.00 |
66.43 |
48 |
Corosolic
acid |
-7.90 |
0.00 |
473.72 |
3.18 |
4.00 |
2.00 |
80.59 |
49 |
Lupenone |
-7.88 |
0.05 |
424.71 |
7.79 |
1.00 |
0.00 |
17.07 |
50 |
Coladin |
-7.88 |
0.17 |
424.54 |
4.92 |
5.00 |
0.00 |
61.83 |
51 |
Abyssinone
III |
-7.88 |
0.19 |
390.48 |
5.90 |
4.00 |
1.00 |
55.76 |
52 |
Neomacrotriol |
-7.85 |
0.06 |
472.75 |
6.63 |
3.00 |
3.00 |
60.69 |
53 |
Abyssinoflavone
V |
-7.85 |
0.06 |
338.36 |
3.53 |
5.00 |
2.00 |
75.99 |
54 |
13-hydroxyfeselol |
-7.85 |
0.06 |
400.51 |
3.53 |
5.00 |
2.00 |
75.99 |
55 |
Assafoetidnol
A |
-7.83 |
0.05 |
398.50 |
3.15 |
5.00 |
2.00 |
75.99 |
56 |
Demethoxyexcelsin |
-7.83 |
0.05 |
384.38 |
3.15 |
7.00 |
0.00 |
64.61 |
57 |
3-taraxasterol |
-7.80 |
0.00 |
430.76 |
9.48 |
1.00 |
1.00 |
20.23 |
58 |
Neoilexonol
acetate |
-7.80 |
0.00 |
484.76 |
7.16 |
3.00 |
0.00 |
43.37 |
59 |
Sipholenol
I |
-7.80 |
0.00 |
508.74 |
3.59 |
6.00 |
4.00 |
102.68 |
60 |
Cabralealactone |
-7.80 |
0.00 |
412.61 |
5.00 |
3.00 |
0.00 |
43.37 |
61 |
Ursolic
acid |
-7.80 |
0.00 |
455.70 |
3.76 |
3.00 |
1.00 |
60.36 |
62 |
Stylopine |
-7.80 |
0.00 |
328.39 |
0.46 |
5.00 |
2.00 |
44.66 |
63 |
Khayanolide
D |
-7.80 |
0.00 |
502.56 |
1.07 |
9.00 |
3.00 |
135.66 |
64 |
Olean-12-en-3-one |
-7.80 |
0.00 |
426.73 |
7.59 |
1.00 |
0.00 |
17.07 |
65 |
Tribulus
saponin aglycone 1 |
-7.80 |
0.00 |
350.54 |
4.75 |
3.00 |
2.00 |
49.69 |
66 |
Foetidin |
-7.80 |
0.00 |
381.49 |
5.47 |
4.00 |
2.00 |
51.83 |
67 |
Samarcandin |
-7.80 |
0.00 |
400.51 |
3.47 |
5.00 |
2.00 |
75.99 |
68 |
Resinone |
-7.80 |
0.00 |
440.71 |
6.94 |
2.00 |
1.00 |
37.30 |
69 |
Uncinatone |
-7.80 |
0.00 |
318.41 |
3.97 |
4.00 |
2.00 |
66.76 |
70 |
Urs-9(11),12-dien-3beta-ol |
-7.80 |
0.14 |
424.71 |
7.17 |
1.00 |
1.00 |
20.23 |
71 |
Sesamin |
-7.78 |
0.05 |
354.36 |
3.22 |
6.00 |
0.00 |
55.38 |
72 |
Euphornin
C |
-7.75 |
0.30 |
546.70 |
4.95 |
8.00 |
1.00 |
116.20 |
73 |
Salmahyrtisol
B |
-7.75 |
0.06 |
386.57 |
4.51 |
3.00 |
1.00 |
46.53 |
74 |
Isoferprenin |
-7.75 |
0.06 |
362.47 |
6.42 |
3.00 |
0.00 |
35.53 |
75 |
(±)-paulownia |
-7.75 |
0.06 |
370.36 |
2.40 |
7.00 |
1.00 |
75.61 |
76 |
Limonin |
-7.75 |
0.06 |
470.52 |
1.03 |
8.00 |
0.00 |
104.57 |
77 |
Sablacaurin
A |
-7.73 |
0.15 |
482.79 |
9.30 |
2.00 |
0.00 |
26.30 |
78 |
Farnesiferol
A |
-7.73 |
0.05 |
384.51 |
3.58 |
4.00 |
1.00 |
55.76 |
79 |
Epilupeol |
-7.70 |
0.00 |
426.73 |
7.65 |
1.00 |
1.00 |
20.23 |
80 |
Lupenone |
-7.70 |
0.00 |
424.71 |
7.79 |
1.00 |
0.00 |
17.07 |
81 |
Sipholenol
A |
-7.70 |
0.00 |
478.76 |
5.38 |
4.00 |
3.00 |
69.92 |
82 |
Taraxasteryl
acetate |
-7.70 |
0.00 |
468.76 |
7.84 |
2.00 |
0.00 |
26.30 |
83 |
Retusolide
B |
-7.70 |
0.00 |
316.44 |
2.95 |
3.00 |
0.00 |
43.37 |
84 |
Cycloart-23Z-ene-3beta,25-diol |
-7.70 |
0.00 |
456.75 |
7.32 |
2.00 |
1.00 |
29.46 |
85 |
7-deacetoxy-7-oxogedunin |
-7.70 |
0.00 |
440.53 |
2.82 |
6.00 |
0.00 |
86.11 |
86 |
Tribulus
saponin aglycone 2 |
-7.70 |
0.00 |
434.66 |
4.18 |
4.00 |
3.00 |
69.92 |
87 |
Lup-20(29)-ene-3beta,23-diol |
-7.70 |
0.00 |
456.75 |
7.05 |
2.00 |
2.00 |
40.46 |
88 |
Beta-boswellic
acid |
-7.70 |
0.00 |
455.70 |
3.93 |
3.00 |
1.00 |
60.36 |
89 |
3-ketotirucall-8,24-dien-21-oic
acid |
-7.70 |
0.00 |
425.63 |
4.43 |
3.00 |
0.00 |
57.20 |
90 |
6-oxoisoiguesterin |
-7.70 |
0.00 |
420.59 |
6.02 |
3.00 |
2.00 |
57.53 |
91 |
Friedelanol
methyl ether |
-7.70 |
0.00 |
470.82 |
8.44 |
1.00 |
0.00 |
9.23 |
92 |
Jamaicin |
-7.70 |
0.00 |
378.38 |
3.73 |
6.00 |
0.00 |
63.22 |
93 |
Calopogonium
isoflavone B |
-7.70 |
0.00 |
348.35 |
3.80 |
5.00 |
0.00 |
53.99 |
94 |
Di-podocarpanoid
hugonone B |
-7.70 |
0.00 |
580.80 |
4.03 |
6.00 |
4.00 |
115.06 |
95 |
3-O-benzoylhosloquinone |
-7.70 |
0.00 |
420.55 |
5.24 |
4.00 |
0.00 |
60.44 |
96 |
Isochamanetin |
-7.68 |
0.05 |
364.40 |
3.80 |
5.00 |
3.00 |
86.99 |
97 |
Oleanolic
acid |
-7.68 |
0.05 |
457.72 |
4.09 |
3.00 |
1.00 |
60.36 |
98 |
Pectachol
B |
-7.68 |
0.05 |
442.55 |
4.29 |
6.00 |
1.00 |
74.22 |
99 |
3-O-benzoylhosloppone |
-7.65 |
0.10 |
420.55 |
4.76 |
4.00 |
1.00 |
63.60 |
100 |
Lup-20(29)-ene-3-acetate |
-7.63 |
0.05 |
467.76 |
5.87 |
2.00 |
0.00 |
40.13 |
101 |
Marmaricin |
-7.63 |
0.05 |
384.51 |
3.93 |
4.00 |
1.00 |
55.76 |
102 |
Calactin |
-7.60 |
0.00 |
532.63 |
0.79 |
9.00 |
3.00 |
131.75 |
103 |
Olibanumol
H |
-7.60 |
0.00 |
460.74 |
5.66 |
3.00 |
3.00 |
60.69 |
104 |
Botulin |
-7.60 |
0.00 |
442.73 |
6.72 |
2.00 |
2.00 |
40.46 |
105 |
Proscillaridin |
-7.60 |
0.00 |
532.67 |
2.09 |
8.00 |
4.00 |
125.68 |
106 |
Ottelione
B |
-7.60 |
0.00 |
312.41 |
3.93 |
3.00 |
1.00 |
46.53 |
107 |
Sesterstatin
7 |
-7.60 |
0.00 |
444.61 |
4.14 |
5.00 |
1.00 |
72.83 |
108 |
Sonchuside
A |
-7.60 |
0.00 |
416.51 |
1.08 |
8.00 |
4.00 |
125.68 |
109 |
3alpha-acetoxyolean-12-en-28-al |
-7.60 |
0.00 |
499.75 |
4.58 |
4.00 |
0.00 |
66.43 |
110 |
Beta-amyrin
acetate |
-7.60 |
0.00 |
468.76 |
7.65 |
2.00 |
0.00 |
26.30 |
111 |
Isoiguesterin |
-7.60 |
0.00 |
408.62 |
5.84 |
2.00 |
1.00 |
37.30 |
112 |
5beta,24-cyclofriedelan-3-one |
-7.60 |
0.00 |
424.71 |
7.29 |
1.00 |
0.00 |
17.07 |
113 |
Sigmoidin
B |
-7.60 |
0.00 |
356.37 |
3.83 |
6.00 |
4.00 |
107.22 |
114 |
Sigmoidin
F |
-7.60 |
0.00 |
422.48 |
5.20 |
6.00 |
3.00 |
96.22 |
115 |
3'-prenylnaringenin |
-7.60 |
0.00 |
338.36 |
4.36 |
5.00 |
3.00 |
86.99 |
116 |
Abyssinin
I |
-7.60 |
0.00 |
368.38 |
3.46 |
6.00 |
2.00 |
85.22 |
117 |
Durmillone |
-7.60 |
0.00 |
378.38 |
3.73 |
6.00 |
0.00 |
63.22 |
118 |
Hugonone
A |
-7.60 |
0.00 |
584.84 |
4.64 |
6.00 |
4.00 |
115.06 |
119 |
3-oxo-12-oleanen-28-oic
acid |
-7.60 |
0.00 |
453.68 |
4.13 |
3.00 |
0.00 |
57.20 |
120 |
Limonyl
acetate |
-7.60 |
0.00 |
514.57 |
1.37 |
9.00 |
0.00 |
113.80 |
|
Flubendazole |
-7.60 |
0.20 |
|
|
|
|
|
|
Diflunisal |
-7.20 |
0.00 |
|
|
|
|
|
|
B92 |
-7.13 |
0.15 |
|
|
|
|
|
|
Pranoprofen |
-6.50 |
0.00 |
|
|
|
|
|
|
Fenoprofen |
-6.18 |
0.05 |
|
|
|
|
|
Table
5 Bioactivity scores of the phytocompounds with
their plant sources
No. |
Phytochemical |
Protease Inhibitory score |
Plant source |
1 |
B92 |
0.50 |
|
2 |
9R-hydroxysarcophine |
0.41 |
Sarcophyton glaucum |
3 |
Beta-boswellic
acid |
0.33 |
Boswellia species |
4 |
Sipholenol
I |
0.3 |
Callyspongia siphonella |
5 |
Olean-12-en-3-
one-28-oic acid |
0.28 |
Albizia gummifera |
6 |
Tribulus
saponin aglycone 2 |
0.26 |
Tribulus species |
7 |
Urs-12-ene-1beta,3beta,11alpha,15alpha-tetraol |
0.25 |
Salvia argentea var. aurasiaca |
8 |
Neoilexonol |
0.23 |
Boswellia carterii |
9 |
Ursolic
acid |
0.23 |
Amaracus akhdarensis |
10 |
3beta-hydroxy-11alpha-methoxyurs-12-ene |
0.22 |
Launaea arborescens |
11 |
1,5-di-O-caffeoylquinic
acid |
0.21 |
Cynara cardunculus |
12 |
Olibanumol
H |
0.21 |
Boswellia carterii |
13 |
Isoadiantol |
0.18 |
Adiantum capillus-veneris |
14 |
Lup-20(29)-ene-3beta,23-diol |
0.18 |
Salvia palaestina |
15 |
Uguenensene |
0.17 |
Vepris uguenensis |
16 |
(+)-7alpha,8beta-dihydroxydeepoxysarcophine |
0.17 |
Sarcophyton auritum |
17 |
Neoilexonol
acetate |
0.17 |
Boswellia carterii |
18 |
Cycloart-23Z-ene-3beta,25-diol |
0.17 |
Euphorbia bupleuroides |
19 |
Taraxasterol |
0.16 |
Calotropis procera |
20 |
Lupeol |
0.16 |
Salvia palaestina |
21 |
Taraxasterol |
0.16 |
Calotropis procera |
22 |
Sonchuside
A |
0.16 |
Launaea arborescens |
23 |
3-O-alpha-L-arabinopyranosyl-echinocystic
acid |
0.15 |
Dizygotheca kerchoveana |
24 |
Epilupeol |
0.15 |
Boswellia species |
25 |
Oleanolic
acid |
0.15 |
Salia triloba |
26 |
Abyssinoflavone
V |
0.14 |
Erythrina abyssinica |
27 |
Isoferprenin |
0.14 |
Ferula communis var. genuina |
28 |
Limonyl
acetate |
0.14 |
Vepris uguenensis |
29 |
3-hydroxycycloart-24-one |
0.13 |
Euphorbia guyoniana |
30 |
Sigmoidin
E |
0.13 |
Erythrina abyssinica |
31 |
Tribulus
saponin aglycone 1 |
0.13 |
Tribulus species |
32 |
Isochamanetin |
0.13 |
Uvaria lucida ssp. lucida |
34 |
Hydroxyhopane |
0.12 |
Azolla nilotica |
35 |
Siphonellinol
C |
0.12 |
Callyspongia siphonella |
36 |
Urs-9(11),12-dien-3beta-ol |
0.12 |
Boswellia carterii |
37 |
Sipholenol
A |
0.12 |
Callyspongia siphonella |
38 |
Calactin |
0.12 |
Pergularia tomentosa |
39 |
3alpha-acetoxyolean-12-en-28-al |
0.12 |
Salvia palaestina |
40 |
Beta-amyrin |
0.11 |
Trichodesma africanum |
41 |
Abyssinone
I |
0.11 |
Erythrina abyssinica |
42 |
Calotropursenyl
acetate B |
0.11 |
Calotropis procera |
43 |
Lupeol
acetate |
0.11 |
Torilis radiata |
44 |
Abyssinone
III |
0.11 |
Erythrina abyssinica |
45 |
3-acetylsesterstatin
1 |
0.1 |
Hyrtios erecta |
46 |
Sigmoidin
F |
0.1 |
Erythrina abyssinica |
47 |
Resinone |
0.09 |
Drypetes gerrardii |
48 |
Euphornin
C |
0.09 |
Euphorbia helioscopia |
49 |
Lucidene |
0.08 |
Uvaria species |
50 |
Calotroproceryl
acetate A |
0.08 |
Calotropis procera |
51 |
Beta-anhydroepidigitoxigenin |
0.08 |
Calotropis procera |
52 |
3-taraxasterol |
0.08 |
Pergularia tomentosa |
53 |
3'-epi-afroside |
0.07 |
Gomphocarpus sinaicus |
54 |
Taraxast-20-ene-3beta,30-diol |
0.07 |
Launaea arborescens |
55 |
5,6-dehydrocalotropin |
0.07 |
Gomphocarpus sinaicus |
56 |
Argeloside
O |
0.07 |
Solenostemma argel |
57 |
Khayanolide
D |
0.07 |
Khaya senegalensis |
58 |
5beta,24-cyclofriedelan-3-one |
0.07 |
Drypetes gerrardii |
59 |
24-methylene
cycloartanol |
0.06 |
Euphorbia helioscopia |
60 |
24-methylencycloartanol |
0.06 |
Euphorbia bupleuroides |
61 |
Limonin |
0.06 |
Vepris glomerata |
62 |
Sesterstatin
7 |
0.06 |
Hyrtios erecta |
63 |
Beta-amyrin
acetate |
0.06 |
Scorzonera undulata |
64 |
Anastatin
B |
0.05 |
Anastatica hierochuntica |
65 |
Scalarolide |
0.05 |
Hyrtios erecta |
66 |
Retusolide
B |
0.05 |
Euphorbia retusa |
67 |
3-O-benzoylhosloquinone |
0.05 |
Hoslundia opposita |
68 |
Lup-20(29)-ene-3-acetate |
0.05 |
Euphorbia helioscopia |
69 |
Neomacrotriol |
0.04 |
Neoboutonia macrocalyx |
70 |
3-acetyltaraxasterol |
0.03 |
Pergularia tomentosa |
71 |
Tingenin
B |
0.03 |
Elaeodendron schlechteranum |
72 |
Friedelane-3,7-dione |
0.03 |
Drypetes gerrardii |
73 |
Taraxasteryl
acetate |
0.03 |
Achillea fragrantissima |
74 |
Abyssinin
I |
0.03 |
Erythrina abyssinica |
75 |
3-oxo-12-oleanen-28-oic
acid |
0.03 |
Ekebergia benguelensis |
76 |
Di-podocarpanoid
hugonone A |
0.01 |
Hugonia busseana |
77 |
20-epi-isoiguesterinol |
0.01 |
Salacia madagascariensis |
78 |
Lupenone |
0.01 |
Diospyros mespiliformis |
79 |
Sablacaurin
A |
0.01 |
Sabal causiarum |
80 |
Lupenone |
0.01 |
Diospyros mespiliformis |
81 |
Hugonone
A |
0.01 |
Hugonia castaneifolia |
Flubendazole |
0.01 |
||
82 |
7-deacetoxy-7-oxogedunin |
0.00 |
Swietenia mahogani |
Pranoprofen |
-0.05 |
||
Fenoprofen |
-0.07 |
||
Diflunisal |
-0.14 |
The results of the pharmacokinetic
assessment of the frontrunner phytocompounds, reference compounds, and
co-crystalized are presented below in figure 2. The results are shown in
bioavailability radar graphics. The components of the pictures below include
Lipophilicity (LIPO), size, polarity (POLAR), solubility (INSOLU), flexibility
(FLEX), and saturation (INSATU). According to the result, the reference
compounds and co-crystalized ligands failed the bioavailability radar test. Out
of the 82 phytocompounds assessment, 18 were within the optimal range of the
bioavailability radar test.