Journal of Taibah University for Science

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In-silico natural product database mining

for novel neuropilin-1 inhibitors: molecular
docking, molecular dynamics and binding energy
computations

Mahmoud A. A. Ibrahim, Sara S. M. Ali, Khlood A. A. Abdeljawaad, Alaa H. M.

Abdelrahman, Gamal A. Gabr, Ahmed M. Shawky, Gamal A. H. Mekhemer,
Peter A. Sidhom, Paul W. Paré & Mohamed-Elamir F. Hegazy

To cite this article: Mahmoud A. A. Ibrahim, Sara S. M. Ali, Khlood A. A. Abdeljawaad, Alaa
H. M. Abdelrahman, Gamal A. Gabr, Ahmed M. Shawky, Gamal A. H. Mekhemer, Peter A.
Sidhom, Paul W. Paré & Mohamed-Elamir F. Hegazy (2023) In-silico natural product database
mining for novel neuropilin-1 inhibitors: molecular docking, molecular dynamics and
binding energy computations, Journal of Taibah University for Science, 17:1, 2182623, DOI:
10.1080/16583655.2023.2182623

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JOURNAL OF TAIBAH UNIVERSITY FOR SCIENCE
2023, VOL. 17, NO. 1, 2182623
https://doi.org/10.1080/16583655.2023.2182623

In-silico natural product database mining for novel neuropilin-1 inhibitors:

molecular docking, molecular dynamics and binding energy computations
Mahmoud A. A. Ibrahim a,b , Sara S. M. Alia , Khlood A. A. Abdeljawaada , Alaa H. M. Abdelrahmana , Gamal A.
Gabrc,d , Ahmed M. Shawkye , Gamal A. H. Mekhemera , Peter A. Sidhomf , Paul W. Parég and
Mohamed-Elamir F. Hegazyh
a Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, Egypt; b School of Health
Sciences, University of KwaZulu-Natal, Durban, South Africa; c Department of Pharmacology and Toxicology, College of Pharmacy, Prince
Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia; d Agricultural Genetic Engineering Research Institute (AGERI), Agricultural Research
Center, Giza, Egypt; e Science and Technology Unit (STU), Umm Al-Qura University, Makkah, Saudi Arabia; f Department of Pharmaceutical
Chemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt; g Department of Chemistry & Biochemistry, Texas Tech University, Lubbock,
TX, USA; h Chemistry of Medicinal Plants Department, National Research Centre, Giza, Egypt

ABSTRACT ARTICLE HISTORY

In the search for new metabolite inhibitors, a natural product activity and species source Received 18 November 2022
(NPASS) database was virtually screened using AutoDock software to identify potential NRP1 Revised 14 February 2023
inhibitors. NPASS compounds complexed with NRP1 were subjected to molecular dynamics (MD) Accepted 16 February 2023
simulations. Furthermore, NPASS-NRP1 binding affinities were calculated using the MM-GBSA KEYWORDS
approach. Based on calculated binding energies, kamolonol (NPC146388) demonstrated lower Cancer; neuropilin-1 (NRP1);
NRP1 binding affinity than the co-crystallized HRG/Arg-1 ligand with binding energy (Gbinding ) docking calculations; MD
values of –34.5 and –32.0 kcal/mol, respectively. Structural and energetic analysis showed high simulations;
stability for kamolonol and HRG/Arg-1 with NRP1 over the 200 ns MD simulations. The studied pharmacokinetic study
physicochemical properties of kamolonol and HRG/Arg-1 revealed that these compounds obey
Lipinski’s rule of five. ADMET characteristics of kamolonol and HRG/Arg-1 were predicted, and
kamolonol showed better ADMET properties compared to HRG/Arg-1. Based on these results,
kamolonol is a promising NRP1 inhibitor worthy of further experimental assays as anti-carcinoma
remediation.

1. Introduction
Biological alteration that results in unregulated cell
growth [1] is referred to as cancer and is a world-
wide health challenge with poor clinical outcomes
[2,3]. Approximately 10 million deaths were reported
in 2020 by global cancer statistics [4]. Despite ongo-
ing progress in surgery and radiotherapy, patients with
advanced tumours still have poor prognoses [5]. More-
over, there is only a small number of newly approved
cancer medications released annually by the US Food
and Drug Administration (FDA) [6]. With resistance to
therapeutic drugs a substantial problem in treating
cancer [7], there is a critical need for novel cancer
therapies.
Numerous cancers, including gastric, urinary, blad-
der, breast, lung, and esophageal, have high levels of
neuropilin-1 (NRP1) protein [8–11]. NRP1 is a cell surface
receptor that binds vascular endothelial growth factor
(VEGF), a potent mediator of endothelial permeabil-
ity, chemotaxis, and proliferation. It is also a regulator
for tumour development, proliferation, invasion, metas-
tases, and prognosis [12–16]. NRP1 enhances angio-
genesis by forming a direct complex with endothelial
growth factors A and 2 (VEGFA and VEGFR2) [17]. It
also promotes the tumour’s development after binding
with the VEGFA due to its ability to promote RhoA acti-
vation [18]. Besides, NRP1 has the ability to accelerate
neoplasm progression by steadying the role of regula-
tory T cells (Tregs) and banning the tumour-associated
macrophages (TAM) from penetrating normoxic cancer
areas [19]. Although NRP1 protein has received consid-
erable critical attention as a potential therapeutic target
for cancer therapy [20,21], no drug has been approved
as an NRP1 inhibitor.
Natural products (NPs) retrieved from microbes and
plants have a vital role in drug discovery, particularly
against carcinoma and contagious illnesses [22,23]. Sev-
eral drugs are natural products from plant sources, such
as paclitaxel, morphine, and vinblastine [24]. There-
fore, there is abundant opportunity for mining novel

CONTACT Mahmoud A. A. Ibrahim m.ibrahim@compchem.net Computational Chemistry Laboratory, Chemistry Department, Faculty of
Science, Minia University, Minia 61519, Egypt; School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000, South Africa; Mohamed-Elamir
F. Hegazy elamir77@live.com Chemistry of Medicinal Plants Department, National Research Centre, 33 El-Bohouth St., Giza 12622, Egypt
Supplemental data for this article can be accessed here. https://doi.org/10.1080/16583655.2023.2182623
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided the original work is properly cited.
2 M. A. A. IBRAHIM ET AL.
anticancer drug candidates as NRP1 inhibitors from the
Natural Product Activity and Species Source (NPASS)
database. In the current study, NPASS database was
screened for promising NRP1 inhibitors utilizing molec-
ular docking computations [25]. Subsequently, promis-
ing NPASS compounds were selected and subjected
to molecular dynamics (MD) simulations and the cor-
responding binding energies were estimated using
the MM-GBSA approach. The stability and tightness
of the most potent NPASS compounds within NRP1
were selected. Thus, the current study highlights the
potentiality of NPASS candidates as NRP1 inhibitors
and illustrates a promising drug candidate for clinical
consideration.
2. Computational methodology
2.1. NRP1 preparation
The neuropilin-1 b1 domain (NRP1) atomic coordinates
in complex with L-homoarginine (HRG/Arg-1) were
retrieved from the protein databank (PDB code: 5ijr;
resolution: 1.52 Å [26]) and considered as a template
for all in-silico computations. The crystallographic water
molecules, ions, and ligand were eliminated from the
NRP1 protein, keeping only the amino acids. The proto-
nation state of the amino acids was investigated using
the H++ server, and all missing hydrogen atoms were
inserted [27].
2.2. Database preparation
The Natural Product Activity and Species Source
(NPASS) database, containing more than 35,000 natural
compounds, was downloaded in SDF format [25]. The
duplicated compounds were eliminated based on the
International Chemical Identifier (InChIKey) [28]. The
three-dimensional (3D) structures of the NPASS com-
pounds were generated using Omega2 software [29,30]
and minimized utilizing the MMFF94S force field inte-
grated inside SZYBKI software [31,32]. The protona-
tion state of the NPASS compounds was examined
using fixpka algorithm within the QUACPAC software,
respectively [33]. The Gasteiger-Marsili method was
used for the determination of the partial charges of
NPASS compounds [34]. The prepared files are present
in a CompChem database (www.compchem.net/ccdb)
that is publically accessible. The schematic diagram of
the utilized computational approaches is depicted in
Figure 1.
2.3. Molecular docking
AutoDock Vina1.1.2 software was used for executing
molecular docking calculations [35]. The NRP1 protein
was converted into pdbqt format using MGL tools (ver-
sion 1.5.7) [36]. The details of the employed protocol
for the docking calculations are described elsewhere
[37–39]. Except the exhaustiveness parameter, which
was set to 50 and 200 in fast and expensive calculations,
respectively, the remaining parameters were preserved
at the default settings. The grid box was tailored to fit
the active site of NRP1 protein by taking the centroid
of HRG/Arg-1 as a centre of the grid, with a grid size of
15 Å × 15 Å × 15 Å and a value of spacing equal to 1 Å.
The grid was centred at 32.485, –11.49, and 27.507 (in
x, y, and z dimensions, respectively). The top nine scor-
ing poses were estimated via visual investigation and
the lowest docking score was selected as a representive
mode.
2.4. Molecular dynamics simulations
The most effective NPASS compounds complexed with
the NRP1 protein underwent molecular dynamics (MD)
simulations using AMBER16 software [40]. The details
of MD simulations are described elsewhere [41–45].
Briefly, the inspected NPASS compounds were defined
utilizing the general AMBER force field (GAFF2) [46],
while the NRP1 protein was characterized using the
AMBER force field of 14SB [47].
MD simulations were conducted employing both
implicit and explicit water solvents. In the implicit water
solvent MD simulations, the atomic partial charges of
the inspected NPASS compounds were estimated using
an AM1-BCC method with the aid of the Antecham-
ber tool within the AMBER16 [48]. Periodic boundary
conditions were not utilized, and the cutoff value was
set to 999 Å. Additionally, the solvent model (igb = 1)
was used to present the solvation contributions [49].
All the investigated systems were first minimized for
500 steps. The minimized complexes were warmed pro-
gressively from 0 to 300 K over 10 ps. Thereafter, the
NPASS-NRP1 complexes were subjected to an equilib-
rium stage of 50 ps, followed by a production stage
of 1 ns.
In explicit water solvent MD simulations, the
restricted electrostatic potential (RESP) approach was
employed to determine the partial charge of each
atom of the inspected NPASS compounds at the HF/6-
31G∗ level of theory [50]. Quantum mechanics cal-
culations were performed using Gaussian09 software
[51]. TIP3P water molecules were utilized to solvate
NPASS-NRP1 complexes in an octahedron box with
a minimal distance of 12 Å [52]. All investigated sys-
tems were minimized by employing 5000 cycles before
heating from 0 to 300 K over 50 ps under the NVT
ensemble. NPASS-NRP1 complexes were then equili-
brated over 1 ns under the NPT ensemble. The equili-
brated coordinates of the systems were subjected to
production runs of 10 and 200 ns. Atomic coordinates
were recorded every 10 ps for post-dynamics analyses
and binding free energy estimations. The Particle Mesh
 JOURNAL OF TAIBAH UNIVERSITY FOR SCIENCE 3

Figure 1. The schematic diagram of the utilized computational approaches in the virtual screening process of the Natural Product
Activity and Species Source (NPASS) database.

Ewald (PME) approach was applied to treat long-range 2.5. MM-GBSA binding energy
electrostatic interactions [53]. Berendsen barostat with
Binding energies of inspected NPASS compounds in
a 2 ps relaxation duration was employed to adjust the
complex with NRP1 were calculated using a molecular
atmospheric pressure [54]. To keep temperature steady
mechanics-generalized Born surface area (MM-GBSA)
at 298 K, Langevin dynamics with gamma_ln set to 1.0
approach [58]. An updated generalized born model
for collision frequency was applied [55]. The SHAKE
including Onufriev (igb = 2) was used for computing
algorithm was applied to constrain all bonds involving
the polar solvation energy [59]. The MM-GBSA binding
hydrogen bonds at the time step of 2 fs [56]. The GPU
energies were computed based on statistically inde-
version of pmemd (pmemd.cuda) was applied to per-
pendent snapshots gathered from MD simulations in
form MD simulations. The molecular visualizations were
accordance with the following equation:
generated with the help of BIOVIA Visual Studio2020
[57]. Gbinding = Gcomplex − (GNPASS + GNRP1 )
4 M. A. A. IBRAHIM ET AL.
The energy term (G) was determined as:
G = GGB + GSA + Eele + Evdw
Through employing generalized born (GB) models, the
electrostatic solvation energy (GGB ) in the abovemen-
tioned equation was determined with GSA standing for
nonpolar solvation-free energy. E ele refers to electro-
static energy. E vdw is van der Waals energy. The entropic
contributions are often disregarded because of high
computational costs [60,61].
2.6. Drug-likeness characteristics
The physicochemical characteristics of the identified
compound were estimated utilizing a SwissADME
online website (http://www.swissadme.ch). The esti-
mated characteristics included topological polar sur-
face area (TPSA), relative molecular weight (MW), num-
ber of hydrogen bond donors (nOHNH), number of
hydrogen bond acceptors (nON), and the partition coef-
ficient (MlogP) [62].
2.7. ADMET characteristics
ADMET properties of the identified compounds were
evaluated by an online pkCSM web server [63]. The
absorption (A) was estimated by human intestinal
absorption (HIA) and Caco-2 permeability. Distribu-
tion (D) was predicted based on blood–brain bar-
rier (BBB) permeability and steady-state distribution
volume (VDss). The metabolism (M) was detected
using CYP3A4 inhibitor/substrate. Excretion (E) is spec-
ified according to the total clearance of the drug.
Finally, the toxicity (T) was determined based on
hepatotoxicity.
3. Results and discussion
3.1. In-silico protocol assessment
The performance of AutoDock Vina1.1.2 software in
predicting the correct ligand-NRP1 binding pose was
assessed. For assessment purposes, the co-crystallized
HRG/Arg-1 inhibitor was re-docked in NRP1 binding
site, and the predicted docking pose was compared
to the experimental binding mode (PDB code: 5ijr
[26]) (Figure 2). As depicted in Figure 2, the dock-
ing pose was similar to the native structure of the
co-crystallized HRG/Arg-1 ligand with an RMSD value
of 0.23 Å. AutoDock Vina results showed a docking
score of –5.6 kcal/mol, forming six significant hydro-
gen bonds with TRP301 (2.01 Å), ASP320 (1.65, 3.11 Å),
SER346 (2.60 Å), GLU348 (2.44 Å), and ILE415 (2.79 Å).
Based on these results, AutoDock Vina software was uti-
lized to screen the NPASS database for potential NRP1
inhibitors.
3.2. Virtual screening of the NPASS database
Molecular docking calculations were executed via two
stages of accuracy that were named fast and expensive
docking stages (see computational methodology
section for details). The NPASS database, containing
greater than 35,000 compounds, was virtually screened
using fast docking computations. The docking scores
of NPASS compounds were predicted and compared
to that of the co-crystallized HRG/Arg-1 ligand (calc.
–5.6 kcal/mol). NPASS compounds with docking scores
< −7.0 kcal/mol were selected and subjected to expen-
sive docking computations, giving a total number
of 1,332 compounds. Due to a large number of
investigated compounds, a threshold value of –7.0
kcal/mol was selected to shortlist the prospective NRP1
inhibitors. Table S1 provides the evaluated fast and
expensive docking scores for the top 1,332 NPASS com-
pounds against the NRP1 protein. Figure S1 depicts 3D
and 2D molecular interactions of the top four potent
NPASS compounds with essential residues within the
active site of the NRP1 protein. Table 1 summarizes the
obtained docking scores, 2D chemical structures, and
binding features of the top four potent NPASS com-
pounds within the active site of NRP1.
Notably, those four NPASS compounds were filtered
according to further binding energy calculations over
10 ns MD simulations. As illustrated in Table 1 and
Figure S1, the four NPASS compounds and HRG/Arg-1
demonstrated approximately the same binding modes
within the NRP1 active site. The most favorable inter-
actions between the identified NPASS compounds and
NRP1 active site were conventional hydrogen bonds
and π -based interactions.
Kamolonol (NPC146388), isolated from F. assafoetida
gum resin [64], belongs to the class of organic com-
pounds known as coumarins. Kamolonol possesses
antiplasmodial characteristics, anti-cellular hypertrophic,
and anti-fibrotic effects [65,66]. Besides, kamolonol
demonstrated a promising docking score towards
NRP1 protein with a value of –9.3 kcal/mol (Table
1). The potency of kamolonol as an NRP1 inhibitor
can be traced to its ability to exhibit multiple hydro-
gen bonds with the key amino acids of the NRP1
active site (Figure 2). Inspecting the binding mode
of kamolonol revealed that the hydroxyl (OH) group
of 2-methylcyclohexan-1-ol ring formed a hydrogen
bond with the carbonyl (C = O) group of ASP320
amino acid with a bond length of 2.68 Å (Figure 2).
Besides, the carbonyl (C = O) group of the methylhex-
anone ring exhibited three hydrogen bonds with the
NH group of ASN313 and GLU348 and NH2 group of
LYS347 with bond lengths of 2.25, 2.41, and 3.01 Å,
respectively (Figure 2). In addition, kamolonol demon-
strated π -donor hydrogen bond with TRP301 residue
and π -alkyl interactions with TYR297 and TYR353
residues.
 JOURNAL OF TAIBAH UNIVERSITY FOR SCIENCE 5

Figure 2. (a) (i) Superimposed structures of the co-crystalized mode (in grey) and the predicted docking pose (in green) and (ii)
2D molecular interaction of L-homoarginine (HRG/Arg-1). (b) (i) 3D and (ii) 2D representations of the predicted binding mode for
kamolonol (NPC146388) within the NRP1 active site. The predicted docking score in kcal/mol is also listed.
6 M. A. A. IBRAHIM ET AL.

Table 1. Computed fast and expensive docking scores (in kcal/mol), 2D chemical structures, and binding features for the top four
potent NPASS compounds against the NRP1 protein.a
Docking Score (kcal/mol)

No. NPASS Code 2D Chemical Structure Fast Expensive Binding Featuresb

HRG/Arg-1c –5.6 –5.7 TRP301 (2.01 Å),
ASP320 (1.65, 3.11 Å),
SER346 (2.60 Å),
GLU348 (2.44 Å),
ILE415 (2.79 Å)

1 NPC146388 (Kamolonol) –9.2 –9.3 ASN313 (2.25 Å),

ASP320 (2.68 Å),
LYS347 (3.01 Å),
GLU348 (2.41 Å)

2 NPC108434 –8.8 –8.9 ASN313 (2.66, 2.15 Å),

GLY318 (2.61 Å)

3 NPC75315 (Stelletin A) –8.8 –8.7 SER298 (2.13 Å),

ASN300 (2.26 Å),
TRP301 (2.28 Å)

4 NPC19013 (Sculponin D) –8.7 –8.7 ASP320 (2.45 Å),

TYR353 (2.36 Å)

a Data ranked based on the expensive docking scores.

b Only hydrogen bonds are listed in Å.
c Reference ligand.

3.3. Molecular dynamics simulations corresponding MM-GBSA binding energies (Gbinding )

were estimated and listed in Table S2. As data enrolled
Molecular dynamics (MD) simulations of the target-
in Table S2, four NPASS compounds demonstrated
inhibitor complex are essential for inspecting confor-
greater binding affinity compared to the co-crystallized
mational steadiness and changes, internal motions,
HRG/Arg-1 ligand (calc. –28.7 kcal/mol) with binding
and the reliability of target-inhibitor binding affinities
energies with values in the range of –21.5 to –29.8
[67,68]. Consequently, MD simulations were employed
kcal/mol. Those four potent NPASS compounds in com-
herein to investigate the stability and binding affin-
plex with NRP1 were subjected to explicit water solvent
ity of the most potent NPASS compounds complexed
MD simulations for 10 ns for more reliable binding affini-
with NRP1 protein. Considering computational cost and
ties. The corresponding binding energies (Gbinding )
time, the top 5% promising NPASS compounds (i.e.
were calculated and illustrated in Figure 3.
67 compounds with expensive docking scores < –8.1
Interestingly, only kamolonol exposed binding
kcal/mol) in complex with NRP1 were subjected to
energy lower than that of the HRG/Arg-1 (calc. –29.8
implicit water solvent MD simulations. Additionally, the
kcal/mol) over the MD course of 10 ns. A MD simulation
 JOURNAL OF TAIBAH UNIVERSITY FOR SCIENCE 7

Figure 3. Estimated MM-GBSA binding energies for the four promising NPASS compounds against the NRP1 active site over 1 ns in
implicit water solvent MD simulations and 10 and 200 ns in explicit water solvent MD simulations.

for kamolonol was also prolonged to 200 ns, and the
corresponding binding energy (Gbinding ) was calcu-
lated (Figure 3). No discernible variation in the predicted
binding energies of kamolonol within the NRP1 active
site over the different simulated times of 10 and 200 ns
MD simulations. Compared to HRG/Arg-1, kamolonol
complexed with NRP1 demonstrated lower binding
energy over 200 ns MD simulation with Gbinding val-
ues equal to –34.5 and –32.0 kcal/mol, respectively
(Figure 3).
Inherent driving forces in the binding of kamolonol
and the HRG/Arg-1 were analyzed utilizing MM-GBSA
binding energy decomposition (Figure 4). Remarkably,
the van der Waals forces (E vdw ) demonstrated a signif-
icant contribution to the binding energy of kamolonol-
and HRG/Arg-1-NRP1 complexes, with values of –38.3
and –32.5 kcal/mol, respectively (Figure 4).
The electrostatic forces (E ele ) were also adequate
for kamolonol and HRG/Arg-1 complexed with NRP1,
with average values of –21.2 and –19.6 kcal/mol,
respectively (Figure 4). The abovementioned findings
give statistical information on the binding energies of
kamolonol as a putative NRP1 inhibitor.
To examine kamolonol-NRP1 interactions and the
contribution of essential residues inside the active
site of NRP1, estimated Gbinding values were divided
into individual amino acid participations (Figure 5a).
Particularly, amino acids with energy contributions
less than –0.5 kcal/mol were depicted in Figure 5a.
Per-residue energy decomposition analysis demon-
strated that TRP301, SER346, ILE415, and ASP320 inter-
acted with kamolonol and HRG/Arg-1 (Figure 5a). For
instance, ASP320 amino acid residue participated in the
total binding energy (Gbinding ) with values of –2.6

Figure 4. MM-GBSA binding energy components for kamolonol (NPC146388) and the co-crystallized HRG/Arg-1 ligand with the
NRP1 protein over the 200 ns MD simulations.
8 M. A. A. IBRAHIM ET AL.
Figure 5. (a) The energy contribution of the most essential amino acids to the total MM-GBSA binding energy and (b) 2D represen-
tations of the anticipated binding modes for (i) kamolonol (NPC146388) and (ii) HRG/Arg-1 with the NRP1 active site in accordance
with the average structure of the 200 ns MD simulations.
and –2.1 kcal/mol, for kamolonol- and HRG-NRP1 com-
plexes, respectively (Figure 5a). The average structures
for kamolonol and HRG/Arg-1 inside the NRP1 active
site over the 200 ns MD simulations are also displayed
in Figure 5b. Kamolonol and HRG/Arg-1 formed four and
two hydrogen bonds, respectively, with the key residues
of the active site of NRP1 protein throughout the 200 ns
MD simulations.
Inspecting the average structure for kamolonol-
NRP1 complex showed that kamolonol demonstrated
essential hydrogen bonds with key amino acid residues
over the MD simulation. Notably, these interactions
were absent in the initial predicted binding modes
from docking computations. This demonstrates the
importance of molecular dynamics simulations toward
reliable results. Among these interactions are hydrogen
bonds with ASP320, ILE415 and GLU348 (Figure 5b).
3.4. Post-dynamics analyses
3.4.1. Binding energy per-frame
To investigate the stability of kamolonol within the
NRP1 active site, the correlation between the binding
energy and simulation time was inspected (Figure 6).
As illustrated in Figure 6, kamolonol and HRG/Arg-1
were generally stable from 32 ns until the termination
of the simulation, demonstrating binding energy equal
to –34.5 and –32.0 kcal/mol, respectively. These study
results elucidated the steadiness of the investigated
complexes throughout the 200 ns MD simulations.

Figure 6. The estimated binding energies of kamolonol (NPC146388) (in red) and HRG/Arg-1 (in black) within the NRP1 protein
during the 200 ns MD simulations.
3.4.2. Hydrogen bond analysis
The hydrogen bonding of the ligands with the NRP1
protein was estimated throughout the MD course of
200 ns. The correlation between the number of hydro-
gen bonds and simulation time was inspected and pre-
sented in Figure S2. The most striking aspect of Figure
S2 is that the average number of hydrogen bonds was
3 and 2 for the kamolonol and HRG/Arg-1. The current
findings clearly supported the steady for the kamolonol
and HRG/Arg-1.
3.4.3. Centre-of-mass distance
Centre-of-mass (CoM) distance was used to inspect
the steadiness of the kamolonol and HRG/Arg-1 within
NRP1. The CoM distance was measured between the
kamolonol and HRG/Arg-1 and the ASP320 residue
over the 200 ns MD simulations (Figure 7). The CoM
distance was steady for kamolonol and HRG/Arg-1
complexed with NRP1 at average distances of 10.7
and 8.6 Å, respectively. The presented results demon-
strated the high stability of kamolonol and HRG/Arg-1
with NRP1.
3.4.4. Root-mean-square deviation
To examine the structural changes of NRP1 after com-
plexation with kamolonol and HRG/Arg-1, the root-
mean-square deviation (RMSD) analysis was measured
(Figure 9). The average RMSD values were 0.13 and
0.10 nm for the kamolonol- and HRG/Arg-1-NRP1 com-
plexes, respectively, over the 200 ns MD simulations
(Figure 8). The RMSD analysis showed that the two com-
plexes preserved their stability until the end of the sim-
ulations. These results confirmed that kamolonol and
JOURNAL OF TAIBAH UNIVERSITY FOR SCIENCE 9
HRG/Arg-1 are tightly bonded and do not disturb the
overall structural constancy of NRP1 besides keeping
structural integrity.
3.5. Drug-likeness characteristics
The SwissADME website was utilized to predict the
drug-likeness characteristics of kamolonol compared
to HRG/Arg-1. For kamolonol the MLogP value was
found to be less than five (calc. 3.0), indicating that
this compound has high lipophilicity. The molecular
weight of kamolonol was found to be less than 500
(calc. 398.49 g/mol). Additionally, the number of hydro-
gen bond acceptors (nON) was 5, and the number
of hydrogen bond donors (nOHNH) was 1 (Figure 9).
The TPSA of the kamolonol was 76.74, which indi-
cates that kamolonol has good bioavailability (Figure
9). Finally, the calculated %ABS was 82.5%, explaining
that kamolonol has good cell membrane permeability
and oral bioavailability. Comparing the drug-likeness
characteristics of kamolonol with those of HRG/Arg-1
demonstrated that kamolonol has better physiochem-
ical properties and oral bioavailability than HRG/Arg-1.
3.6. ADMET characteristics
The pharmacokinetic properties of kamolonol were
predicted and compared to HRG/Arg-1 utilizing the
pkCSM online server. The pharmacokinetic proper-
ties included absorption, in which kamolonol demon-
strated high Caco2 permeability (calc. 0.839) and high
human intestinal absorption (HIA) (calc. 98.3), suggest-
ing that kamolonol would be highly absorbed (Table 2).
10 M. A. A. IBRAHIM ET AL.

Figure 7. CoM distance (in Å) of kamolonol (NPC146388) (in red) and HRG/Arg-1 (in black), and ASP320 of NRP1 protein active site
over the 200 ns MD simulations.

Figure 8. RMSD of the backbone atoms from the first frame of kamolonol (NPC146388) (in red) and HRG/Arg-1 (in black) with NRP1
protein during the simulation time of 200 ns.

In contrast to HRG/Arg-1, HRG/Arg-1 manifested poor
Caco2 permeability and HIA with values of –0.351 and
24.6, respectively (Table 2). To examine the drug dis-
tribution, the VDss value was expected with values of
0.351 and –0.438 for kamolonol and HRG/Arg-1, respec-
tively (Table 2). The metabolism results showed that
kamolonol could work as an inhibitor for the CYP3A4
enzyme; however, HRG/Arg-1 was not an inhibitor for
the CYP3A4 enzyme (Table 2). The excretion was pre-
dicted based on the total clearance with values of 0.433
and 0.589 for kamolonol and HRG/Arg-1, respectively
(Table 2). According to hepatotoxicity, both kamolonol
and HRG/Arg-1 were not toxic (Table 2). The most
striking observation to emerge from the data compar-
ison was the superior ADMET features for kamolonol
over HRG/Arg-1. These findings confirmed that the
kamolonol could be used as a promising anticancer
drug candidate.
3.7. Kamolonol vs. EG00229
EG00229, (S)−2-(3-(benzo[c][1,2,5]thiadiazole-4-sulfon
amido)thiophene-2-carboxamido)−5-guanidinopenta
noic acid, is an experimental inhibitor of NRP1 with
 JOURNAL OF TAIBAH UNIVERSITY FOR SCIENCE 11

Figure 9. Predicted physiochemical characteristics of kamolonol (NPC146388) and HRG/Arg-1 as NRP1 inhibitors.

Table 2. The expected ADMET properties for the kamolonol (NPC146388) and HRG/Arg-1.
Absorption (A) Distribution (D) Metabolism (M) Excretion (E) Toxicity (T)
Caco2 Permeability Human Intestinal CYP3A4
NPASS Code (cm/s) Absorption (HIA) VDss (human) Inhibitor/Substrate Total Clearance Hepatotoxicity
Kamolonol (NPC146388) 0.839 98.3 0.351 Yes 0.433 No
HRG/Arg-1 –0.351 24.6 –0.438 No 0.589 No

IC50 value of 3 μM [69]. To estimate the prospectivity
of the identified NPASS compound, the binding score
and mode of EG00229 towards NRP1 protein were eval-
uated and compared to kamolonol (NPC146388). Fur-
thermore, MD simulations over 200 ns pursued by bind-
ing affinity estimations were performed for EG00229
complexed with NRP1 (Table 3 and Figure S3). As
depicted in Figure S3, the docking pose of EG00229
within the binding pocket of NRP1 was similar to the
binding mode of kamolonol, exhibiting seven hydrogen
bonds with ASP320 (2.54, 2.68 Å), SER346 (2.78, 2.82 Å),
THR349 (1.91 Å), and ILE415 (2.96, 3.01 Å). Compared to

Table 3. Predicted docking score (in kcal/mol) and MM/GBSA binding energies during the 200 ns MD course for kamolonol and
EG00229 complexed with NRP1 protein.
Calculated MM/GBSA binding energy (kcal/mol)
NPASS Code/Name Docking Score (kcal/mol) E vdw E ele E GB E SUR Ggas GSolv Gbinding
Kamolonol (NPC146388) –9.3 –38.3 –21.2 29.7 –4.8 –59.5 25.0 –34.5
EG00229 –6.1 –30.0 –18.8 23.3 –3.1 –48.9 20.2 –28.7
12 M. A. A. IBRAHIM ET AL.
kamolonol (docking score = −9.3 kcal/mol), EG00229
demonstrated a good docking score against NRP1 with
a value of −6.1 kcal/mol (Table 3).
To gain more reliable results, EG00229 in complex
with NRP1 was subjected to 200 ns MD simulations, and
the corresponding MM-GBSA binding affinity was com-
puted (Table 3). From Table 3, the average MM-GBSA
binding energy (Gbinding ) for EG00229 in complex with
NRP1 was –28.7 kcal/mol, compared to –34.5 kcal/mol
for the kamolonol-NRP1 complex. Similar to kamolonol,
the binding affinity of EG00229 complexed with NRP1
protein was predominated by van der Waals (E vdw ) with
an average value of –30.0 kcal/mol (Table 3).
4. Conclusion
In the current study, the NPASS database contain-
ing more than 35,000 natural products was virtu-
ally screened against the NRP1 protein for identify-
ing potent inhibitors as anticancer drug candidates
using the molecular docking technique. Based on
docking computations, 67 compounds with expen-
sive docking scores < –8.1 kcal/mol in complex with
NRP1 were subjected to MD simulations. The com-
puted MM-GBSA binding energy over an MD course
of 200 ns demonstrated superior binding affinity of
kamolonol (NPC146388) compared to the HRG/Arg-1
ligand with NRP1, demonstrating Gbinding values of
–34.5 and –32.0 kcal/mol, respectively. During 200 ns
MD simulations, energetic and structural analyses indi-
cated perfect constancy for the kamolonol. Further-
more, kamolonol elucidated favorable physiochemical
and pharmacokinetic properties compared to HRG/Arg-
1. Finally, these results confirmed that the kamolonol
could be used as a promising NRP1 inhibitor and hold
promise for further experimental assays toward cancer
treatment.
Acknowledgements
Ahmed M. Shawky would like to thank the Deanship of Sci-
entific Research at Umm Al-Qura University for supporting
this work by Grant Code: (22UQU4331174DSR43). The com-
putational work was completed with resources supported
by the Science and Technology Development Fund (STDF-
Egypt, Grants No. 5480 and 7972), and Bibliotheca Alexandrina
(http://hpc.bibalex.org). Dr. Mahmoud A. A. Ibrahim extends
his appreciation to the Academy of Scientific Research and
Technology (ASRT), Egypt, for funding Graduation Projects
conducted at CompChem Lab, Egypt.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
This work was supported by Umm Al-Qura University: [grant
no 22UQU4331174DSR43].
Data availability statement
The data that support the findings of this study are available
in the Supporting Information Material of this paper.
ORCID
Mahmoud A. A. Ibrahim http://orcid.org/0000-0003-4819-
2040
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