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Docking Study of Ligands Targeting NLRP3 Inflammatory Pathway for

Endodontic Diseases

Article in Chemical Methodologies · January 2023

DOI: 10.22034/CHEMM.2022.367137.1623

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 Chemical Methodologies 7(2023) 200-210

Journal homepage: http://chemmethod.com

Original Research Article

Docking Study of Ligands Targeting NLRP3 Inflammatory

Pathway for Endodontic Diseases
Emine Erdag1,* , Meltem Kucuk2, Umut Aksoy2, Nurettin Abacioglu3, Ahmet Ozer
Sehirli4
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Near East University, Lefkosa TRNC, Mersin10,
Turkey
2Department of Endodontics, Faculty of Dentistry, Near East University, Lefkosa TRNC, Mersin10, Turkey
3Department of Pharmacology, Faculty of Pharmacy, Near East University, Lefkosa TRNC, Mersin10, Turkey
4Department of Pharmacology, Faculty of Dentistry, Near East University, Lefkosa TRNC, Mersin10, Turkey

ARTICLE INFO ABSTRACT

Article history The NLRP3 (NOD-like receptor family containing a pyrin domain 3)
inflammasome pathway has a crucial role in the dental immune system and
Submitted: 2022-10-24
is associated with the activation of the dental immune response. Therefore,
Revised: 2022-11-13
it is a specific target for drug molecules to be selected in the treatment of
Accepted: 2022-12-06 endodontic diseases. Various NLRP3 inflammatory and caspase-1
Manuscript ID: CHEMM-2210-1623 inhibitors that exhibit effective inhibition against inflammatory conditions
Checked for Plagiarism: Yes have been identified in previous studies. In this study, the human NLRP3
Language Editor: model was constructed by the loop modeling method using computer-
Dr. Fatimah Ramezani aided programs. Binding affinities, inhibition constants (Ki), and ligand-
Editor who approved publication: protein interactions of the selected ligands were calculated and
Dr. Mohammad S. Mubarak investigated by molecular docking simulation against the inflammasome
NLRP3 and caspase-1. Binding modes and calculations were performed
according to Lamarckian genetic algorithm. The calculated docking scores
DOI:10.22034/CHEMM.2022.367137.1623 for each ligand used in this study were between the range of -5.1 and -11.8
KEYWORDS kcal/mol for the inhibitory activity. CY-09 (a NLRP3 inflammasome
inhibitor) and VX-765 (a caspase-1 inhibitor) were shown to have the most
NLRP3 inflammasome inhibition desirable binding affinities, Ki values, and strong binding interactions in the
Caspase-1 inhibition NLRP3 and human caspase-1 binding pockets, respectively. The
Endodontic diseases combination of CY-09 and VX-765 ligands can be used to prevent
Molecular docking inflammation in the treatment of endodontic diseases. These inhibitors
could be used in the future treatment of endodontic infections and to
improve the viability of root canal drugs and pulp capping materials.

GRAPHICAL ABSTRACT

* Corresponding author: Emine Erdag

 E-mail: [email protected]
© 2023 by SPC (Sami Publishing Company)
 Erdag E., et al. / Chem. Methodol., 2023, 7(3) 200-210
Introduction of two motifs termed Walker A and Walker B [8].
The Walker A site (P-loop) is responsible for the
Endodontic disease is defined as the
ATPase activity. Since it is an important part of
immunoinflammatory response of the pulp or
the ATP-binding site, it could be used as a target
periapical tissues against endodontic pathogens
for in silico studies of new NLRP3 inhibitors [8].
exhibiting various virulence factors associated
LPS and LTA can stimulate Toll-like receptors
with host infection [1]. Lipopolysaccharides
(TLR4 type) that activate the nuclear factor
(endotoxin, LPS) and lipoteichoic acid (LTA) are
kappa light chain enhancer of activated B cells
considered as the most important virulence
(NFκB) and promote expression of NLRP3, IL-1β,
factors because they have the highest
and IL-18 [9]. A recent study has highlighted that
immunogenicity in terms of pulp or periapical
the NLRP3 inflammasome plays a crucial role in
tissue damage [2]. Innate immune cells possess
triggering the dental immune response and may
surface receptors known as pattern recognition
represent a specific target for the treatment of
receptors (PRRs) that recognize two subclasses
endodontic diseases [10].
of molecules termed pathogen-associated
Therefore, the aim of this molecular docking
molecular patterns (PAMPs) and damage-
study was to evaluate the binding energies and
associated molecular patterns (DAMPs). The
interactions of different inhibitors known to play
NOD-Like receptors (NLRs), one of the cytosolic
an important role in inflammation through the
PRRs, recognize PAMP signals and can form an
direct interaction of NLRP3 binding sites or
inflammatory complex called inflammasome [3].
through the inhibition of caspase-1, and also to
The inflammasome is a protein complex that
select the most effective combination for use in
recognizes stimuli with potential to cause
the endodontic treatment or as a complementary
inflammation and, in response, initiates the
combination for the main strategy of endodontic
production of pro-inflammatory cytokines (IL-1β
treatment. Our selected inhibitors could be used
and IL-18) through the activation of caspase-1
simultaneously to prevent inflammasome
[4].
complex formation, caspase-1 activity, and pro-
Furthermore, caspase-1 generates pro-
Gasdermin-D cleavage leading to cellular
Gastermin-D, and then transmembrane
pyroptosis and a range of inflammatory
Gastermin-D pores are formed to induce cell
responses aggravating the endodontic diseases.
death [5]. Although there are different types of
inflammasome structures, the NLRP3
Materials and Methods
inflammasome (NOD-like receptor family
containing a pyrin domain 3) has been reported Preparation of data set
to be associated with pulpitis and apical A human NLRP3 model and docking calculation
periodontitis [5]. Therefore, NLRP3 is involved in based on the crystal structure of rabbit
the dental immune system and is activated by nucleotide-binding oligomerization domain-
many bacterial stimuli [6]. The NLRP3 consists of containing protein 2 (NOD2) in the ADP-bound
3 main parts; the N-terminal pyrine effector state (PDB ID: 5IRM) and the alignment
domain (PYD), the NACHT domain [NAIP insertions closer to the binding site were built by
(neuronal apoptosis inhibitor protein), CIITA (an loop modelling using Modeller 9.15 software
activator of transcription protein), HET-E (a locus [11], and then the created model was prepared
protein), and TP1 (telomerase-associated for molecular docking. On the other hand, the
protein)] as well as one Leucine-rich repeat crystal structure of the peptide NLRP3-PYD (PDB
domain (LRR) [7]. The LRR domain, located at the ID: 3QF2) and the crystal structure of Caspase-1
carboxy terminus, recognizes microbial ligands (PDB ID: 1RWK) were downloaded from the
and endogenous hazardous molecules [7]. The Protein Data Bank (PDB) of the Research
NACHT domain is involved in the oligomerization Collaboratory for Structural Bioinformatics
of the NLRP3 inflammasome and consists mainly (RCSB). A selection of specific ligands for each

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macromolecule was performed prior to the inhibit the designed human NLRP3 model,
docking process. The previously reported NLRP3 NLRP3-PYD domain, and Caspase-1 protein. The
inflammasome inhibitors, CY-09 (PubChem CID grid box sizes were set to 25 × 25 × 28 A◦ for all
44561595) [12], 3,4-methylenedioxy-β- docking studies. The most favourable docking
nitrostyrene (MNS) (PubChem CID 672296) [13], poses were represented by the binding affinity
OLT1177 (Dapansutrile) (PubChem CID (ΔG). Subsequently, the inhibition constant (Ki)
12714644) [14], Oridonin (PubChem CID and the molecular interaction of the selected
5321010) [15], Tranilast (PubChem CID poses were evaluated. The structures of proteins,
5282230) [16], and MCC950 (PubChem CID ligands, and docking complexes were visualized
9910393) [17] were preferred for the molecular using the Discovery Studio 3.0 software. When
docking study of the human NLRP3 model. On the molecular docking is performed with a rigid
other hand, the specific inhibitors of the NLRP3- receptor, the accurate visualization of ligand and
PYD domain, BAY 11-7082 (PubChem CID receptor interactions may not always be
5353431) [18] and 16673-34-0 (PubChem CID achieved. To overcome this limitation, multiple
85542) [19], were chosen as ligands for the molecular docking programs can be used with
NLRP3-PYD peptide. Furthermore, the previously different algorithms and molecular dynamics
described caspase-1 inhibitors [5], Parthenolide simulations.
(PubChem CID 7251185) and Belnacasan (VX-
765) (PubChem CID 11398092) were used as Results and Discussion
ligands for the caspase-1 docking process. Before In general, the binding affinities of all ligands
docking, the structures of all ligands were were favorable between the range -5.1 and -11.8
downloaded from the PubChem database and kcal/mol. On the other hand, the predicted Ki
converted into the mol2 file format using the values of all ligands were in the nanomolar (nM)
Open Babel 3.1 software. range, indicating good binding properties, since
ligands with smaller inhibition constants bind
Structure refinement, molecular docking and
more tightly to their target macromolecule [22].
interaction analysis
Thus, the lower the Ki values, the higher the
For structure refinement, all water molecules and binding affinity of the ligands.
hetero-atoms were removed from the protein The interacting residues, types of interactions,
structure, polar hydrogens were added, non- binding affinities, and inhibition constant values
polar hydrogens were merged, and Gasteiger of the ligands 16673-34-0 and BAY117082
charges were assigned. After refinement, they against the peptide NLRP3-PYD are summarized
were converted into PDBQT file format via in Table 1.
AutoDockTools4 [20]. Autodock 4.0 software was The docking results show that both ligands bind
used for molecular docking studies to predict the to the type I site of the NLRP3-PYD peptide,
ligand binding modes selected in its associated mainly through hydrogen bonding, alkyl and π-
target macromolecule. For the ligands to be alkyl interactions as shown in Figure 1.
energetically favourable and for the correct In addition, VX-765, a caspase-1 inhibitor,
arrangement of the molecules in space to be appears to have better binding affinity compared
determined, the energy should be minimized. For with another caspase-1 inhibitor, Parthenolide, as
the minimization process, the AutoDock software listed in Table 2. In the docking process of VX-765
uses the Lamarckian genetic algorithm [21]. A and Parthenolide, the common amino acid
conformal cluster analysis was performed residues involved in the interaction in the
allowing for a root mean square deviation caspase-1 binding pocket were revealed as
(RMSD) of 2.0 Å on the docked results. The Arg383, His342, Met345, Val348, and Gly346
docking study was performed separately to with electrostatic interactions as shown in Figure
evaluate the selected antagonists known to 2.

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Table 1: Critical amino acid residues of NLRP3-PYD peptide active site interacting with selected inhibitors, their
binding affinities, and inhibition constants
Binding Affinity, ΔG Inhibition
Name of Inhibitor Amino Acid Residues
(kcal/mol) Constant, Ki (nM)
16673-34-0 -6.6 4.55 Ser5, Arg7, Cys8, Thr56
BAY-117082 -5.1 5.64 Ser5, Arg7, Thr 56

Figure 1: The 2D and 3D binding interactions of BAY-117082 (A) and 16673-34-0 (B) against peptide NLRP3-
PYD (PDB ID: 3QF2). The green dotted lines denote hydrogen bonds between ligands and amino acids, whereas
pink lines denote hydrophobic interactions. The red line indicates an unfavourable donor-donor

Table 2: Critical amino acid residues of caspase-1 active site interacting with selected inhibitors, their binding
affinities, and inhibition constants
Binding Affinity, ΔG Inhibition
Name of Inhibitor Amino Acid Residues
(kcal/mol) Constant, Ki (nM)
Val184, His342,
VX-765 -7.6 3.25 Met345, Gly346,
Val348, Ile354, Arg383
His342, Met345,
Parthenolide -6.4 4.28 Gly346, Val348, and
Arg383

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Figure 2: The 2D and 3D binding interactions of VX-765 (C) and Parthenolide (D) against Caspase-1 (PDB ID:
1RWK). The green dotted lines denote hydrogen bonds between ligands and amino acids, whereas pink lines
denote hydrophobic interactions

Figure 3: The 2D and 3D binding interactions of MCC950 (E), Tranilast (F), and MNS (G) against human NLRP3
model. The green dashed lines represent hydrogen bonds between compounds and amino acids, whereas
pink/purple lines represent hydrophobic interactions. Electrostatic interactions are shown as orange lines

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Figure 4: The 2D and 3D binding interactions of OLT1177 (H) and Oridonin (I) against human NLRP3 model.
The green dotted lines denote hydrogen bonds between ligands and amino acids, whereas pink lines denote
hydrophobic interactions

In addition, MCC950, Tranilast, Oridonin, MNS, the ligands Oridonin, MNS and OLT1177 have
and OLT1177 were found to interact with human fewer interactions with related residues at the
NLRP3 binding sites mainly through electrostatic binding site and weaker binding affinities
forces. The 2D representation of molecular compared with CY-09, MCC950, and Tranilast.
interactions for these ligands is shown in Figures The activation pathway of the NLRP3
3 and 4. inflammasome is an important process initiating
Among other ligands, CY-09 has better binding cell pyroptosis in apical periodontitis or pulpitis
affinity and inhibition constant as summarized in [23]. When NLRP3 is activated, it associates with
Table 3. Aside from hydrogen bonding, alkyl, and apoptosis-associated speck-like protein (ASC)
π-π stacking interactions, CY-09 generates a π- and pro-caspase-1 to form the NLRP3-
sulfur interaction with Tyr435 and a halogen inflammatory complex [24]. ASC is a cytosolic
(fluorine) bond with Thr233, which are protein composed of a C-terminal caspase
considered to be significant for activity. The 3D recruitment domain (CARD) and a pyrin domain
representation of the human NLRP3 model (PYD). NLRP3 interacts with ASC in the resulting
constructed with 2D interactions of CY-09 at the complex. As a result, pro-caspase-1 and caspase-1
binding site is shown in Figure 5. In addition, are activated, respectively. [24]. Caspase-1
Tranilast interactions indicate that Thr233 and activation cleaves pro-IL-1β and pro-IL-18 into
Tyr232 residues are required for the CY-09-like their mature forms, IL-1β and IL-18 [24]. The
inhibitory activity. In addition, MCC950, a active form of caspase-1 also causes the cleavage
diarylsulfonylurea compound, has the second of Gasdermin D (GSDMD) at the N terminus [25].
desired docking score in terms of binding affinity. Thus, GSDMD is an inflammatory caspase
Unlike CY-09, MCC950 has some interactions substrate responsible for the formation of pores
with various amino acid residues such as Arg314, in the cell membrane for pyroptotic cell death
Asp362, Glu363, and Arg406, mainly via Van der that occurs in apical periodontitis and pulpitis
Waals and hydrogen bonds. On the other hand, [25].

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Figure 5: The 3D representation of created human NLRP3 model with 2D representation of the ligand CY-09
(yellow, in space-filling calotte model view) in the binding pocket

Pyroptosis, an inflammatory cell death, can occur inflammatory diseases [29]. However, studies on
due to the IL-1β release, and the effect of IL-1β the effect of NLRP3 inhibitors on the apical
production on pyroptotic processes was periodontitis and pulpitis are rare. Previous
examined in a periodontal disease study [26]. As studies have examined whether MCC950 blocks
indicated in the NLRP3 inflammasome activation IL-1β and caspase-1 activation in mouse and
pathway (Figure 6), the accumulated IL-1β plays human macrophages and have been shown to
a key role in a number of inflammatory responses inhibit ASC oligomerization [29]. Peng et al.
affecting the pathology of apical periodontitis and recently demonstrated that MCC950
pulpitis. IL-1β can stimulate osteoclastogenesis downregulates the NLRP3 inflammasome
through the kappa-B core ligand (RANKL) and signaling pathway in human periodontal ligament
expression of matrix metalloproteinases (MMPs) cells, thereby reducing the production of the pro-
[27]. In addition to these effects, IL-1β stimulates inflammatory cytokines IL-1β and IL-18,
the release of the pro-inflammatory mediators IL- resulting in inhibition of osteogenesis [30]. Due
6 and IL-8 from periodontal fibroblasts, leading to its specificity for NLRP3, MCC950 could be
to bone resorption [28]. Currently, in addition to preferred for chronic and acute inflammation. As
the prevailing therapeutic strategies for apical it reduces the production of IL-1β and IL-18,
periodontitis and pulpitis, the importance of MCC950 can be considered as a potential
NLRP3 inflammasome activation and caspase-1 therapeutic in the treatment of apical
inhibitors in endodontic treatments to treat IL- periodontitis and pulpitis. Furthermore, some
1β-related pyroptotic problems should be selective caspase-1 inhibitors such as Belnacasan
emphasized. NLRP3 inflammasome inhibitors, (VX-765) are currently used to block caspase-1
which contribute to IL-1β maturation, are activity in inflammatory diseases, including
currently used as a treatment for many periodontitis [31].

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Figure 6: The signalling pathway for the activation of NLRP3 inflammasome in endodontic infections (Figure
created in the Mind the Graph platform: https://mindthegraph.com).

Concerning the previous studies on the NLRP3 the NLRP3-PYD domain. Therefore, they are
inflammasome pathway, some NLRP3 and expected to play an important role in the
caspase-1 inhibitors were selected and a inhibitory activity of the selected ligands.
molecular docking study was performed for each In the established human model of NLRP3, amino
ligand. The selected inhibitors were ranked and acid residues in the ADP-binding site overlap
scored according to their target proteins. The with residues previously reported to be
interactions of the ligands with their target important for the inhibitory activity [33]. These
proteins, the binding free energies, and the amino acid residues located at the ADP-binding
inhibition constants were compared. The value of site of the NOD2-ADP-bound structure (PDB:
the inhibitor constant (Ki) is an indicator of 5IRM) are Ile231, Tyr232, Thr233, Asn235,
determining the strength of a strong an inhibitor. Ser283, Gly284, Lys285, Ser286, Thr287, Phe427,
Consistent with our results, ligands with higher Pro466, and His58333. To inhibit the ATPase
binding affinities have lower inhibitor constant activity, Tyr232 and Thr233 residues present in
values. Therefore, low Ki values indicate that less the Walker A motif of the NACHT domain have
drug is required for the inhibitory activity. been shown to be significant [33]. The CY-09
In a recent study, Moasses et al. examined the interactions with Tyr232 and Thr233 residues
interfaces specified for the homo-interaction of can be related to its high inhibitory activity.
the NLRP3-PYD domain [32]. Concerning Tranilast, on the other hand, is a tryptophan
previous in silico studies reported in the analogue that binds directly to NLRP3 with
literature, the interacting amino acid residues similar binding interactions as CY-09. As
found at each site were given as Ser5, Arg7, Cys8, demonstrated in a previous study, Asp362 and
Ala11, Glu15, Asp50, Val52, Asp53, and Thr56 Glu363 are key residues in the Walker B motif of
[32]. Our results indicate that our ligands 16673- the NACHT domain, implying the inhibition of
34-0 and BAY-117082 interact with active-site ATP hydrolysis [34]. Based on the results, the
residues Ser5, Arg7, Cys8, and Thr56 of the PYD MCC950 interactions with Asp362 and Glu363
domain. These specified amino acid residues have residues appear to be important to keep the
been included in key residues for the type I site of NLRP3 inflammasome in an inactive state.

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 Erdag E., et al. / Chem. Methodol., 2023, 7(3) 200-210
Furthermore, Arg341 has been identified as a key ORCID:
amino acid residue for the structural domain of Emine Erdag
the caspase-1 protein-binding pocket [35]. The https://orcid.org/0000-0002-1431-935X
docking results of VX-765 and Parthenolide
indicate that their interactions with residues References
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HOW TO CITE THIS ARTICLE

Emine Erdag, Meltem Kucuk, Umut Aksoy, Nurettin Abacioglu, Ahmet Ozer Sehirli. Docking Study of Ligands Targeting
NLRP3 Inflammatory Pathway for Endodontic Diseases. Chem. Methodol., 2023, 7(3) 200-210
https://doi.org/10.22034/CHEMM.2022.367137.1623
URL: http://www.chemmethod.com/article_162985.html

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