Nitric Oxide Production Inhibitors from Vietnamese Knema globularia : An in Vitro and in Silico Study

Abstract

Objective: The Knema genus contains various naturally occurring secondary metabolites with pharmacological potential, including antitumor, neuroprotective, antidiabetic, and hepatoprotective activities. This study focuses on identifying nitric oxide production inhibitors from Vietnamese Knema globularia. Methods: The secondary metabolites were isolated using several chromatographic techniques. Their chemical structures were determined using nuclear magnetic resonance (NMR) spectroscopy and compared with published literature. The anti-inflammatory effect was evaluated using the Griess assay, and protein interactions were investigated through docking studies. Results: Based on their anti-inflammatory activity, six compounds (1-6) were isolated from Vietnamese K. globularia. These compounds were identified as lupeol (1), formononetin (2), isoliquiritigenin (3), 2-[4-(3-hydroxypropyl)-2-methoxyphenoxy]propane-1,3-diol (4), (+)-catechin (5), and (−)-epicatechin (6). For the first time, compounds 1, 3, and 4 were reported from Vietnamese K. globularia. All isolated compounds were tested against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophage RAW264.7 cells to assess their anti-inflammatory potential. Compound 5 exhibited the highest inhibitory activity, with an IC₅₀ value of 5.61 μM, followed by compounds 3 and 6, with IC₅₀ values of 6.76 and 11.52 μM, respectively. However, compounds 1, 2, and 4 showed inactivity with IC₅₀ values exceeding 30 μM. Molecular docking was then employed to investigate the affinity and interactions between compounds 3, 5, and 6 and proteins involved in inflammation, such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and interleukin-8 (IL-8), along with ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions. Conclusion: These findings suggest that the active constituents derived from Vietnamese K. globularia have the potential as anti-inflammatory agents worthy of further exploration and development.

Keywords

inflammation NO production cytotoxic RAW264.7 cells molecular docking

Introduction

The genus Knema belongs to the family Myristicaceae and consists of small to medium-sized trees found primarily in the tropical regions of Southeast Asia, China, India, Australia, and Africa. These plants are well-known in traditional medicine and pharmacy.¹ In modern research, Knema species possess many important pharmacological properties, including antitumor, antibacterial, anti-inflammatory, neuroprotective, antidiabetic, antioxidant, and hepatoprotective.² Phytochemical studies of Knema species demonstrated that this genus contains a diverse range of naturally secondary metabolites substances, such as phenols, flavonoids,³ aceto-phenones,⁴ lignans, polyketides, sterols, terpenoids, quinones, and stilbenoids.^5,6

Knema globularia (synonym Knema corticosa), one of the most important species of the Knema genus, is also called “maucho” in the local Vietnamese dialect. Its seeds are famous for curing scabies⁶ and other skin diseases, especially in traditional usage.⁷ Additionally, the stem bark is used as a blood tonic.⁸ Several phytochemicals were isolated from the barks, seeds, and roots of this plant, such as quercetin and kaempferol glycosides,⁹ proanthocyanidin, luteolin, taxifolincatechin, 7-megastigmene-36,9 triol, 3′,4′,6′-trihydroxyaurone, β-sitosterol, daucosterol,¹⁰ kneglobularic acid A and B, kneglobularone A, 6-tridecylsalicylic acid, and kneglomeratanone A.¹¹ To the best of our knowledge, none of the chemical substances derived from K. globularia was known for inhibitory effect despite all scientific efforts. The results regarding the anti-inflammatory effects of Knema genus extracts and chemical components are limited due to several research difficulties, with only a few results of substances obtained from K. furfuracea showing NO inhibitory effect.¹² This research lays the groundwork for the NO inhibition effect of extractions and chemical compositions from Vietnamese K. globularia by identifying study gaps needed to determine the anti-inflammatory aspects for further investigations.

Results and Discussion

Chemical Structure Identifications

The EtOAc fraction was subsequently subjected to column chromatography (CC) using silica gel to isolate six secondary metabolites (1-6) (Figure 1 and the Supplemental Materials). The chemical structures of these compounds were identified as follows: lupeol (1),¹³formononetin (2),¹⁴ isoliquiritigenin (3),¹⁵ 2-[4-(3-hydroxypropyl)-2-methoxyphenoxy]propane-1,3-diol (4),¹⁶ (+)-catechin (5),^17,18 and (−)-epicatechin (6).^17,18

Figure 1.

Structure of compounds 1 − 6 from Vietnamese K. globularia.

Anti-Inflammatory Activity

In the initial experiment, a cytotoxicity assay was conducted to establish the safe and non-toxic concentrations of the isolated compounds (1-6) for subsequent assays. The results indicated that the isolated compounds exhibited no toxicity to RAW 264.7 cells at concentrations below 100 μM, with cell viability consistently maintained at over 90%, as determined by the MTS assay.¹⁹ Consequently, concentrations ranging from 3 to 30 μM were chosen for further investigation (Figure 2), excluding the 100 μM concentration due to its observed cytotoxic effects. This careful selection ensures the reliability of subsequent assays while avoiding potential adverse effects on cell viability.

Figure 2.

The impact of LPS stimulation on cell viability in the presence of compounds 1–6. Cell viability was assessed using the MTS assay and presented as a percentage relative to the control group without the addition of the indicated compounds 1–6. The data are represented as the mean ± SD (n = 3). Significance levels are denoted as *p < 0.05 and **p < 0.01 compared to the control group.

To evaluate the inhibitory activity on NO production, RAW 264.7 cells were exposed to varying concentrations (1-30 μM) of the isolated compounds, and the level of NO production was measured using the Griess reaction.¹⁹ As shown in Table 1, compounds 3, 5, and 6 exhibited the most potent inhibitory activity, with IC₅₀ values of 11.52, 5.61, and 6.76 μM, respectively. In contrast, compounds 1, 2, and 4 demonstrated inactivity, with IC₅₀ values exceeding 30 μM. The positive control, sappanone A, effectively reduced LPS-induced NO production, with an IC₅₀ value of 8.34 μM. These findings underscore the significant inhibitory potential of compounds 3, 5, and 6 against NO production, indicating their promising role as anti-inflammatory agents.

Table 1.

NO Production Inhibition in RAW264.7 Cells of Isolated Compounds (1 − 6).

Compounds	IC₅₀ value (μM)^a
1	> 30
2	> 30
3	11.52 ± 1.92*
4	> 30
5	5.61 ± 1.12*
6	6.76 ± 1.78*
Sappanone A^b	8.32 ± 0.02

^a The inhibitory effects are represented as the molar concentration (μM) giving 50% inhibition (IC₅₀) relative to the vehicle control; Values are mean ± S.D (n = 3); ^b Positive control; *p < 0.05 compared with the control group.

The control group was not exposed to either LPS or the samples. Therefore, any observed inhibitory effects of these compounds on NO production were not influenced by cytotoxic impacts. Upon stimulation with LPS (1 µg/mL), the control group exhibited an approximately 13-fold increase in NO production after 24 h. In contrast, compounds 3, 5, and 6 displayed a dose-dependent reduction in NO production 24 h following LPS stimulation (Figure 3).

Figure 3.

Inhibitory effect of compounds 3, 5, and 6 on LPS-induced NO production in RAW264.7 cells. RAW264.7 cells were pretreated with various concentrations (1, 3, 10, and 30 μM) of the tested compounds for 1 h, followed by treatment with LPS (1 μg/mL), and then incubated for 24 h. Control values were obtained in the absence of both LPS and the compound. The data are presented as the mean ± SD (n = 3). Significance levels are indicated as *p < 0.05 and **p < 0.01 compared to the control group.

Molecular Docking

Three compounds (3, 5, and 6) and positive control-sappanone A (Ligand REF) which known for their significant activity were selected for detailed molecular docking simulations to elucidate their primary mechanisms of action as anti-inflammatory agents. The molecular docking studies focused on the interactions between these compounds and three specific targets: iNOS, COX-2, and IL-8, which are key inflammatory targets. The best-docked poses of the ligands are depicted in Figure 4, highlighting their interactions with the protein. The free binding energies of the ligands were also calculated using AutoDock Vina, providing the basis for assessing the affinity of the ligands toward the iNOS target (Table 2). Both compounds 3 and 5 formed hydrogen bonds with Tyr347 and Arg388, while compound 6 showed no hydrogen interactions with the protein of iNOS. The most impressive free binding energy was observed for compound 5 (−7.1 kcal/mol) when compared to compounds 3 and 6, while the binding energy of positive control-sappanone A was −7.3 kcal/mol. Additionally, this ligand formed two hydrophobic interactions with Asp382 and Arg388.

Figure 4.

Compounds and iNOS interactions.

Table 2.

Docking Results Toward the iNOS.

Compound	Docking score (kcal/mol)	Hydrogen bond	Hydrophobic interaction
3	−6.9	Tyr347, Arg388	Glu377, Arg381, Asp382
5	−7.1	Tyr347, Arg388	Asp382, Arg388
6	−6.8		Ala282, Tyr373, Arg388
Sappanone A	−7.3	Arg388, Ile462	Arg381, Trp463

The docking simulations of the COX-2 protein with the three studied ligands unveiled the potential of these compounds as COX-2 inhibitors, owing to the robust interactions observed between the ligands and residues in the receptor's active site. Figure 5 showcases the optimal docking poses of the ligands, highlighting their binding interactions with the receptor. Additionally, the free binding energies of the ligands were calculated using AutoDock Vina, providing a basis for evaluating the affinity of the ligands towards the COX-2 target (Table 3).

Figure 5.

Compounds and COX-2 interactions.

Table 3.

Docking Results Toward the COX-2.

Compound	Docking score (kcal/mol)	Hydrogen bond	Hydrophobic interaction
3	−8.2	His39, Cys41, Asn43, Cys47, Lys468	Pro153, Lys468
5	−8.2	His39, Cys47, Pro156	Cys36, Val46, Cys47, Pro153, Pro156
6	−9.3	Cys47	Cys47, Leu152, Pro153, Arg469
Sappanone A	−8.9	Thr212	Ala202, His207, His386

Interestingly, there was a similarity in the value of free binding energy of compounds 3 and 5 toward the COX-2 receptor, which was −8.2 kcal/mol. These two ligands were also predicted to form the most hydrogen bonds and hydrophobic interactions, respectively. Specifically, there were five hydrogen bonds formed between compound 3 and some residues in the COX-2 protein active pocket as His39, Cys41, Asn43, Cys47, and Lys468. Some hydrophobic interactions were found between compound 5 and Cys36, Val46, Cys47, Pro153, and Pro156. Compound 6 showed the potential of COX-2 inhibitor with the lowest free binding energy of −9.3 kcal/mol when compared to compounds 3, 5 and positive control-sappanone A (−8.9 kcal/mol). One hydrogen bond was formed between this ligand and Cys47. Besides, four hydrophobic interactions were found between compound 6 and the residues of Cys47, Leu152, Pro153, and Arg469.

Figure 6 presents the optimal docking poses of the ligands, elucidating their binding interactions with the IL-8 receptor. Furthermore, the free binding energies of the ligands were computed using AutoDock Vina, serving as a foundation for evaluating the affinity of the ligands towards the IL-8 target (Table 4).

Figure 6.

Compounds and IL-8 interactions.

Table 4.

Docking Results Toward the IL-8.

Compound	Docking score (kcal/mol)	Hydrogen bond	Hydrophobic interaction
3	−5.3	Gln6, Val39, Glu46	Glu22, Arg24, Ile38, Lys40, Glu46
5	−5.8	Lys9	Lys9, Ile38, Glu46, Leu47, Cys48
6	−5.7	Leu3, Leu7	Ile26, His31
Sappanone A	−5.7	Arg4, Cys5, Glu46, Cys48	Leu3, Ile38, Cys48

Both compound 3 and 5 were predicted to form five hydrophobic interactions with the target protein. Specifically, compound 3 displayed hydrophobic interactions with Glu22, Arg24, Ile38, Lys40, and Glu46, while compound 5 exhibited interactions with Lys9, Ile38, Glu46, Leu47, and Cys48. Their free binding energies were −5.3 and −5.8 kcal/mol, respectively. Compound 6 interacted with the IL-8 protein through two hydrogen bonds, located at Leu3 and Leu7, along with two hydrophobic interactions with Ile26 and His31.

ADMET Predictions of Studied Compounds

The “Lipinski's rule of five” has long been utilized to assess the druggability of a compound. In this study, the three investigated compounds including compounds 3, 5, and 6 possess molecular weights smaller than 500 Daltons. Furthermore, the number of hydrogen bond donors and acceptors for these compounds does not exceed 5 and 10, respectively. Additionally, their log P values are below 5. These observations suggest no violation of the classic Lipinski's rule,²⁰ indicating favorable drug-like properties for the studied compounds.

Moreover, the number of rotatable bonds, total polar surface area (TPSA), and aqueous solubility (log S) were evaluated as part of assessing physicochemical parameters. For optimal oral bioavailability and intestinal absorption, the number of rotatable bonds and the TPSA value should not exceed 10 and 140 Å², respectively.²¹ According to the predicted results by SwissADME, the number of rotatable bonds and TPSA values for these compounds fall within favorable ranges, indicating good physicochemical properties. The log S values of these compounds are −3.70, −2.22, and −2.22, respectively, indicating their solubility. The characteristics of the studied compounds are comprehensively presented in Table 5.

Table 5.

Physicochemical Properties Analyzed with SwissADME.

Compound	MW (g/mol)	Log P	nHBD	nHBA	TPSA	MR	Log S	nRotB
3	256.25	2.37	3	4	77.76	72.32	−3.70	3
5	290.27	0.83	5	6	110.38	74.33	−2.22	1
6	290.27	0.83	5	6	110.38	74.33	−2.22	1

MW: molecular weight; log P: log of octanol/water partition coefficient; nHBD: number of hydrogen bond donor(s); nHBA: number of hydrogen bond acceptor(s); TPSA: total polar surface area; MR: molar refractivity; log S: log of solubility; nRotB: number of rotatable bond(s).

Table 6 presents the in silico predictions of ADME for the three investigated compounds. The range of log skin permeability (log Kp) values spans from −7.82 to −5.61. All compounds are predicted to demonstrate high gastrointestinal absorption. Additionally, both compounds 5 and 6 are projected to be unable to penetrate the blood-brain barrier. They are also forecasted to not inhibit several cytochrome P enzymes, including CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4. Moreover, they are suggested to be substrates of P-glycoprotein (P-gp), in contrast to compound 3.

Table 6.

ADME Predictions Computed by SwissADME.

Compound	Log K_p (cm/s)	GI Abs	BBB per	Inhibitor Interaction
Compound	Log K_p (cm/s)	GI Abs	BBB per	P-gp substrate	CYP1A2 Inhibitor	CYP2C19 Inhibitor	CYP2C9 Inhibitor	CYP2D6 Inhibitor	CYP3A4 Inhibitor
3	−5.61	High	Yes	No	Yes	No	Yes	No	Yes
5	−7.82	High	No	Yes	No	No	No	No	No
6	−7.82	High	No	Yes	No	No	No	No	No

Furthermore, the DL-AOT prediction server was employed to calculate the LD₅₀ values of compounds 3, 5, and 6, resulting in values of 3.68, 3.61, and 3.61, respectively. According to the predicted results (Table 7), all compounds are classified into the “Caution” group.

Table 7.

Toxicity Predicted by DL-AOT Prediction Server.

Compound	LD₅₀ (mg/kg)	Toxicity
3	3.68	Caution
5	3.61	Caution
6	3.61	Caution

While our study focused exclusively on inhibiting NO production, it did not assess other inflammatory agents such as prostaglandin E2 (PGE2) or proinflammatory cytokines like ILs, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ). Moreover, we did not investigate the inhibitory mechanisms at a molecular level using techniques such as western blotting to assess iNOS and COX-2. Despite these limitations, our study yielded positive outcomes, including the isolation of compounds 1, 3, and 4 for the first time from Vietnamese K. globularia, evaluation of isolated compounds on NO inhibitory activity, and docking studies. These novel findings will serve as the groundwork for more comprehensive studies in the future.

Conclusions

The investigation of phytochemicals in K. globularia stem bark from Vietnam yielded the isolation and structural elucidation of six compounds: lupeol (1), formononetin (2), isoliquiritigenin (3), 2-[4-(3-hydroxypropyl)-2-methoxyphenoxy]propane-1,3-diol (4), (+)-catechin (5), and (−)-epicatechin (6). Notably, this study reports the first identification of compounds 1, 3, and 4 from Vietnamese K. globularia. These compounds were evaluated for their anti-inflammatory activity by assessing their ability to inhibit NO production induced by LPS in macrophage RAW264.7 cells. Among the compounds tested, compound 5 exhibited the most potent inhibitory activity, with an IC₅₀ value of 5.61 μM. This was followed by compounds 3 and 6, which showed IC₅₀ values of 11.52 and 6.76 μM, respectively. However, compounds 1, 2, and 4 were inactive, with IC₅₀ values exceeding 30 μM. In consistency with the results from the in vitro assay, molecular docking was conducted. The results revealed compound 3 as an inhibitor of iNOS, COX-2, and IL-8 receptors, with binding free energies of −6.9, −8.2, and −5.3 kcal/mol, respectively. For compound 5, the binding free energies were −7.1, −8.2, and −5.8 kcal/mol, while for compound 6, the energies were −6.8, −9.3, and −5.7 kcal/mol, respectively. This research enhances our understanding of the potential pharmacological applications of compounds derived from Vietnamese K. globularia in the context of inflammation-related conditions.

Material and Methods

General Experimental Procedure

The ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were acquired using a Varian Unity Inova 400 MHz spectrometer (Varian, Inc., California, USA). For column chromatography (CC), all solvents, analytical purposes, and visualization were described in Supplemental Materials.

Plant Material

The stem bark of Vietnamese K. globularia was gathered from Son La province, Vietnam, in May 2021. Botanical identification was expertly conducted by Nguyen Quoc Binh, PhD, of the Vietnam National Museum of Nature, Vietnam Academy of Science and Technology (VAST). To ensure traceability, a voucher specimen (KC-SB-2710) was meticulously archived at the Natural Product Research and Development Lab, Phenikaa University, Vietnam.

Extraction and Isolation

The dried powdered stem bark of Vietnamese K. globularia (2.0 kg) was subjected to reflux extraction using methanol (MeOH, 8.0 L × 3 times) for 1 h. The extraction and isolation scheme was described in detail in Supplemental Materials.

Biology

Cell culture, cell viability assay, and determination of NO production were experimented with according to the methods described in Supplemental Materials.

Molecular Docking Study

Protein and ligand preparation for molecular docking and molecular docking²² were experimented with according to the methods described in Supplemental Materials.

ADMET Predictions of Studied Compounds

All three studied compounds were screened based on “Lipinski's rule of five”.²⁰ SwissADME web tool was used to calculate data relating to the pharmacokinetics of these compounds.²³ In the case of acute oral toxicity prediction, a DL-AOT prediction server was applied.²⁴

Statistical Analysis

Data are presented as the mean ± standard deviation (SD). Graphs were generated, and statistical analyses were conducted using SigmaPlot 6.0 and SigmaStat 3.1 (Systat Software, San Jose, CA, USA). For the analysis, ANOVA followed by Tukey's test on pre-validated data was employed. Alternatively, Prism (GraphPad Software, San Diego, CA, USA) was used for comparisons between two groups, utilizing an unpaired Student's t-test. For comparisons involving more than two groups, the one-way nonparametric ANOVA with Tukey's test followed by Bonferroni post hoc analysis or correlation analysis, as appropriate was used. Statistical significance levels were set at *p < 0.05; **p < 0.01.

Supplemental Material

sj-docx-1-npx-10.1177_1934578X241280043 - Supplemental material for Nitric Oxide Production Inhibitors from Vietnamese Knema globularia: An in Vitro and in Silico Study

Supplemental material, sj-docx-1-npx-10.1177_1934578X241280043 for Nitric Oxide Production Inhibitors from Vietnamese Knema globularia: An in Vitro and in Silico Study by Dao Cuong To, Phu Chi Hieu Truong, Phi-Hung Nguyen, Le Minh Hoang, Hoa Thi Nguyen, Truong Thi Viet Hoa, Truong Thi Thuy Nhung, Phuong Dai Nguyen Nguyen, Ngu Truong Nhan and Manh Hung Tran in Natural Product Communications

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financially supported by the Vietnam Academy of Science and Technology under the grant number: UDPTCN 03/21-23.

Ethical Approval

Ethical approval is not applicable to this article.

Statement of Human and Animal Rights

This article does not contain any studies with human or animal subjects.

Statement of Informed Consent

There are no human subjects in this article, and informed consent is not applicable.

ORCID iDs

Dao Cuong To

Phi-Hung Nguyen

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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