In silico Studies of Potential Drug-like Compounds from various Medicinal Plants: The Discovery of JAK1 Inhibitors and JAK3 Inhibitors

 

Ahmad Dzulfikri Nurhan¹, Maria Apriliani Gani², Jamal Nasser Saleh Al-Maamari², Mahardian Rahmadi¹, Chrismawan Ardianto¹, Junaidi Khotib¹*

¹Department of Pharmacy Practice, Faculty of Pharmacy, Universitas Airlangga, Surabaya 60115, Indonesia.

²Doctoral Programme of Pharmaceutical Sciences, Faculty of Pharmacy,

Universitas Airlangga, Surabaya 60115, Indonesia.

 

ABSTRACT:

Allergic asthma is a chronic respiratory disease mediated by immunoglobulin E (IgE) and T helper type 2 (Th2) cells. Janus kinase 1 (JAK1) and JAK3, which are interleukin-4 signaling components, are crucial in Th2 cell differentiation. Thus, inhibition of JAK1 and JAK3 is a promising therapeutic target to treat allergic asthma. This study explores the potential of secondary metabolites from various medicinal plants to be developed as JAK1 inhibitors and JAK3 inhibitors through in silico studies. In silico drug-likeness and pharmacokinetic characteristics prediction were performed on 106 secondary metabolites from various medicinal plants using the SwissADME online tool. Molecular docking was carried out on 60 medicinal plant metabolites with characteristics that met the drug-likeness criteria by targeting the Janus kinases family proteins (JAK1, JAK2, JAK3, TYK2) using AutoDockVina software. For the results, a total of ten medicinal plant metabolites, namely aloe emodin; genistein; daidzein; glycitein; apigenin 7,4’-dimethyl ether; laburnetin; formononetin; afrormosin; kaempferol; and isothankunic acid, met the criteria for drug-likeness, had an excellent pharmacokinetic profile, and had appropriate binding energy to the target protein JAK1. Then, as many as three medicinal plant metabolites, namely madasiatic acid; madecassic acid; and lupeol also met the criteria for drug-likeness, had an excellent pharmacokinetic profile, and had proper binding energy to the target protein JAK3. In conclusion, this study was found that several medicinal plant metabolites potential to be developed as JAK1 inhibitors and JAK3 inhibitors.

 

 

 

INTRODUCTION: 

Asthma is a group of global health problems that affect at least 300 million people worldwide, with an increasing prevalence and impact profile in many countries^1,2. Based on this, asthma still poses a complex burden on the health system and is often categorized as one of the most prevalent chronic diseases in the world^3,4. In the clinical scope, asthma is divided into two phenotypes: allergic asthma and nonallergic asthma⁵.

 

 

Allergic asthma is the most common asthma phenotype affecting up to 90% of pediatric asthma patients and up to 50% of adult asthma patients^5-7.

 

Recently, the understanding of the etiology and pathogenesis of allergic asthma continues to develop⁸. This multifactorial disease is known to be formed due to a complex interaction between genetic factors and host susceptibility and environmental factors (aeroallergens such as house dust mites, grass pollen, and animal dander)⁹. IgE-mediated immunological responses play a vital role in the pathogenesis of allergic asthma. In addition, the Th1/Th2 paradigm in allergic asthma implies that there is a shift in the immune response from Th1 to Th2^8,10,11. In this regard, the response of Th2 cells is thought to play a dominant role in the emergence of various pathological changes observed in the airways, primarily based on the cytokines they produce^8,10.

 

In terms of treatment, pharmacotherapy and immunotherapy are effective treatment approaches with a wide range of evidence support. However, several studies have revealed that many allergic patients turn to complementary therapies due to concerns about the side effects caused by long-term use of pharmacotherapy and immunotherapy^12,13. Several studies have confirmed that various medicinal plants, including Aloe vera, Centella asiatica, Musa paradisiaca, Passiflora foetida, Rhodomyrtus tomentosa, and Solanum nigrum contain compounds with antiallergic effects^14-20. However, it is not yet fully understood which secondary metabolites produce this antiallergic effect and the underlying mechanism.

 

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is a signal transduction pathway of various cytokines and growth factors¹⁶. The JAK family consists of JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2), while the STAT family consists of STAT1, STAT2, STAT3, STAT5A/B, and STAT6²¹. It is now well known that JAK2, TYK2, and STAT4, which are components of IL-12 signaling, are essential factors in the differentiation of naive T cells into Th1 cells^22,23. Meanwhile, JAK1, JAK3, and STAT6, which are components of IL-4 signaling, are important factors in the differentiation of naive T cells into Th2 cells that play a crucial role in the pathological state of allergic asthma^22,23. Thus, a compound that selectively inhibits JAK1 or JAK3 has tremendous implications for treating allergic asthma.

 

Based on the explanation above, this research explored the derivative compounds of various medicinal plants, including Aloe vera, Centella asiatica, Musa paradisiaca, Passiflora foetida, Rhodomyrtus tomentosa, and Solanum nigrum to be developed as selective JAK1 inhibitors and JAK3 inhibitors to eradicate allergic asthma.

 

MATERIALS AND METHODS:

Ligands Selection and Preparation:

The ligands used in this study are secondary metabolites from various medicinal plants, including Aloe vera, Centella asiatica, Musa paradisiaca, Passiflora foetida, Rhodomyrtus tomentosa, and Solanum nigrum. A total of 106 secondary metabolites of these medicinal plants were obtained from the KNApSAcK Family database (http://www.knapsackfamily.com). In silico screening for drug-likeness was carried out based on Lipinski's rule of five (RO5) and pharmacokinetic characteristics predictions of 106 secondary metabolites using the SwissADME online tool (http://www.swissadme.ch)^24,25. The compounds that met the drug-likeness criteria were further prepared with the following steps: (1) drawn as 2D molecular structures using ChemDraw Professional 15.0 software; (2) copied to Chem3D 15.0 software for shaping and optimizing 3D molecular structures, and then saved as .pdb files; and (3) prepared by removing water molecules, protonated, and added gasteiger charge using AutoDockTools-1.5.6 software and saved in. pdbqt format for further evaluation using a molecular docking study^26,27.

 

Target Proteins:

The target protein used for the molecular docking study was JAK1 (PDB ID: 5WO4 which contains the co-crystal ligand 3-[(4-chloro-3-methoxyphenyl)amino]-1-[(3R,4S-4-cyanooxan-3- yl]-1H-pyrazole-4-carboxamide), JAK2 (PDB ID: 4BBE which contains the co-crystal ligand N-[4-[2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-4-yl] phenyl]ethanamide), JAK3 (PDB ID: 6AAK which contains the co-crystal ligand 4-[[(1S,3R)-5-oxidanyl-2-adamantyl]amino]-1H-pyrrolo[2,3-b]pyridine- 5-carboxamide), and TYK2 (GDP ID: 4GJ3 containing the co-crystal ligand 2,6-dichloro-4-cyano-N-[2-({[(1R,2R)-2-fluorocyclopropyl]carbonyl}amino)pyridine- 4-yl]benzamide) The four target proteins were obtained from the Protein Data Bank (https://www.rcsb.org) and stored in .pdbqt format.

 

Binding Sites Selection and Validation in Target Proteins:

The chain for each target protein for the molecular docking study was selected based on the chain having the pocket binding site with the highest drug scores evaluated using the DoGSiteScorer (http://dogsite.zbh.uni-hamburg.de). The higher the drug score at a pocket binding site, the higher the tendency of the drug to occupy the pocket binding site. Binding sites in selected chains were validated by docking co-crystal ligands to each protein. Then, the root means square deviation (RMSD) was evaluated by comparing the docked form of these co-crystal ligands after three docking replications using PyMOL version 2.3.4. The grid box of co-crystal ligands is validly used as a binding site for the docking target if the RMSD obtained is < 2 because it is categorized as a good solution²⁸.

 

Molecular Docking:

Molecular docking was carried out on secondary metabolites from various medicinal plants that met the drug-likeness criteria by targeting the Janus kinase family proteins (JAK1, JAK2, JAK3, and TYK2) using AutoDockVina. Secondary metabolites from various medicinal plants that have the potential to be developed as JAK1 inhibitors are defined as secondary metabolites that have better binding energy values ​​than co-crystal ligands on JAK1 protein but not on JAK2, JAK3, and TYK2 proteins. Likewise, secondary metabolites from medicinal plants that have the potential to be developed as JAK3 inhibitors are defined as secondary metabolites that have better binding energy values ​​than co-crystal ligands on JAK3 proteins but not on JAK1, JAK2, and TYK2 proteins. Furthermore, interactions between potential secondary metabolites with JAK1 or JAK3 were visualized using Discovery Studio Visualizer v17.2.016349^29-31.

 

RESULT:

Selected Ligands:

Based on the drug-likeness evaluation, it was found that 60 out of 106 secondary metabolites from various medicinal plants met Lipinski's RO5, with details of 30 secondary metabolites from Aloe vera, 11 secondary metabolites from Centella asiatica, 3 secondary metabolites from Musa paradisiaca, 7 secondary metabolites from Passiflora foetida, 7 secondary metabolites from Rhodomertus tomentosa and 3 secondary metabolites from Solanum nigrum.

 

Figure 1. Cartoon representation of (A) JAK1, (B) JAK2, (C) JAK3, (D) TYK2 proteins with their pocket binding sites as a targeted docking. Proteins are represented by blue ribbons, and pocket binding sites are identified by light gold.

 

Selected Binding Sites in Target Proteins:

In JAK1 protein, pocket binding sites with the highest drug score (0.81) were found in chain A. Then, the validation results of JAK1 protein showed that the mean ±standard deviation of the RMSD after three replications was 0.512 ± 0.230 Å (RMSD < 2 Å). In JAK2 protein, pocket binding sites with the highest drug score (0.80) were found in chain A. Then, the validation results of JAK2 protein showed that the average ± standard deviation of the RMSD after three replications was 0.638 ± 0.509 Å (RMSD < 2 Å). In JAK3 protein, pocket binding sites with the highest drug score (0.80) were found in chain D. Then, the validation results of JAK3 protein showed that the mean ± standard deviation of the RMSD after three replications was 0.019 ± 0.008 Å (RMSD < 2 Å). In TYK2 protein, pocket binding sites with the highest drug score (0.81) were found in chain A. Then, the validation results of TYK2 protein showed that the mean ± standard deviation of the RMSD after three replications was 0.082 ± 0.027 Å (RMSD < 2 Å).

 

Based on the RMSD values for all proteins, the solution formed is classified as a good solution category. The structure of each target protein and its pocket binding sites is visualized in Figure 1, and the grid boxes used are shown in Table 1.

 

Table 1. Selected grid boxes of JAK1, JAK2, JAK3, and TYK2 as targeted docking.

 

Potential JAK1 Inhibitors from Various Medicinal Plants:

Based on the molecular docking study, it was found that there were 10 out of 60 secondary metabolites from various medicinal plants, namely: aloe emodin; genistein; daidzein; glycitein; apigenin 7,4'-dimethyl ether; laburnethin; formononetin; afrormosin; kaempferol; and isothankunic acid had potential to be developed as JAK1 inhibitors. These potencies were because these secondary metabolites had good interactions with JAK1 protein but not with JAK2, JAK3, and TYK2 proteins, proving that the yielded binding energy was lower than the binding energy of the binding energy co-crystal ligand in JAK1 (less than equal to - 8.1 kcal/mol). Overall, the binding energy values of each potential JAK1 inhibitor are shown in Table 2. The interaction between each potential JAK1 inhibitor and the JAK1 protein is visualized in Figure 2.

 

 

Table 2. Drug likeness, pharmacokinetics properties prediction, and binding energy values of each potential secondary metabolites of medical plants to be developed as JAK1 inhibitors.

 

 

Figure 2. Binding interactions between potential medical plants' secondary metabolites developed as JAK1 inhibitors with the JAK1 protein.

 

Table 3. Drug likeness, pharmacokinetic properties prediction, and binding energy values of each potential secondary metabolites of medical plants to be developed as JAK3 inhibitors.

 

Figure 3. Binding interactions between potential medical plants' secondary metabolites developed as JAK3 inhibitors with the JAK3 protein.

 

 

DISCUSSION:

Janus kinase (JAK) is a protein involved in the pathological conditions of various diseases. However, the functional role of the JAK family proteins varies depending on the type of disease^32-35. Thus, the development of JAK inhibitors that are selective against disease indications of interest is a major factor in therapy success. JAK1 and JAK3, which are components of IL-4 signaling, have crucial implications for the manifestation of allergic asthma^22,23. The development of a compound that has the potential to act as selective JAK1 inhibitors or selective JAK3 inhibitors is a promising approach to develop complementary therapies for allergic asthma. In this study, an in silico approach was used to evaluate secondary metabolites derived from various medicinal plants that have the potential to be developed as novel and selective JAK1 inhibitors or JAK3 inhibitors.

 

Based on the findings obtained, as many as ten secondary metabolites of medicinal plants include: aloe emodin; genistein; daidzein; glycitein; apigenin 7,4'-dimethyl ether; laburnetin; formononetin; afrormosin; kaempferol; and isothankunic acid has the potential to be developed as novel and selective JAK1 inhibitors. Aloe emodin is an anthraquinone derivative compound. A recent study reported that aloe emodin has activity as a mast cell stabilizer through activating the mitochondrial calcium uniporter, which has positive implications for allergic conditions³⁶. These findings strengthen the results of the in silico study in this study so that further research and development of aloe emodin are promising. Genistein is a flavonoid compound that is known to have various biological activities. In a study on a mouse model of allergic asthma, it was found that genistein ameliorates allergic airway inflammation through the transcription factors T-bet, GATA-3, and STAT-6³⁷. Our in silico study reinforces those findings while also providing insight that the resulting airway inflammation amelioration effect may also be via inhibition of JAK1. Daidzein is one of the most potent isoflavones. A study of a mouse model of allergic encephalomyelitis showed that daidzein reduced the extent of demyelination and disease severity³⁸. The results of the in silico study in this study provide an overview of the potential interaction between daidzein and JAK1 protein, which may have pharmacological activity as a therapy against allergic asthma.

Glycitein is an isoflavone compound that is known to have anti-inflammatory and antioxidant activity. Interestingly, an in vitro study confirmed that glycitein regulates dendritic cell function and suppresses allergic sensitization to peanuts³⁹. These findings complement the results of our in silico analysis that glycitein has the potential to be developed as an antiallergic therapy, especially to treat allergic asthma. Apigenin 7,4'-dimethyl ether (ADE) is known to have activity in inhibiting α-glucosidase and α-amylase enzymes. In addition, in mouse pre-adipocyte (3T3L1) cell lines, it was found that ADE produces a hypolipidemic effect by reducing lipid droplet content in a dose-dependent manner⁴⁰. Laburnetin is an isoflavonoid compound that shows significant activity against Mycobacterium tuberculosis, against fungi, against gram-positive and gram-negative bacteria⁴¹. Interestingly, the potential effects of ADE and laburnetin in the pathological condition of allergic asthma have not been extensively explored. Thus, our findings serve as a starting point for further development of ADEs to treat allergic asthma, particularly through inhibiting the JAK1 protein.

 

Formononetin is an isoflavone phytoestrogen that has been shown to attenuate allergic reactions by inhibiting epithelial-derived cytokines by regulating E-cadherin⁴². Another study confirmed that formononetin relieves inflammation and oxidative stress in the airways in a mouse model of allergic asthma⁴³. These in silico findings complement previous in developing the potential of formononetin as anti-allergic asthma, especially regarding its potential as a JAK1 inhibitor. Afrormosin is also an isoflavone phytoestrogen which has been confirmed by a study that has activity in modulating the inflammatory response in stimulated human neutrophils in vitro⁴⁴. Although neutrophils play an important role in the pathological state of allergic asthma, not many studies have evaluated the effectiveness of aformosin in the treatment of allergic asthma. Thus, further development of afrormosin to treat allergic asthma, especially regarding its potential as a novel JAK1 inhibitor, is wide open.

 

Kaempferol, a flavonoid compound with antioxidant properties, has been studied as an anti-inflammatory and anti-allergic agent. An in vitro study using IgE-stimulated RBL-2H3 cells and Caco-2 cells revealed that kaempferol suppresses IgE-mediated allergic inflammation. Another study in a mouse model of allergic asthma showed that kaempferol reduced eosinophil infiltration and airway inflammation⁴⁵. These findings, which are strengthened by our findings, form the basis for further exploration of kaempferol as a JAK1 inhibitor that may also play a role in the anti-allergic activity produced. Isothankunic acid is a secondary metabolite found in the tropical, medicinal plant Centella asiatica⁴⁶. So far, no studies have evaluated the potential of isothankunic acid as a treatment for allergic asthma or as a JAK1 inhibitor. Our results support exploring the benefits of isothankunic acid for treating allergic asthma through the interaction of isothankunic acid with the JAK1 protein.

 

Furthermore, this in silico study also found that as many as three secondary metabolites from medicinal plants have the potential to be developed as JAK3 inhibitors, namely: madasiatic acid; madecassic acid; and lupeol. Like isothankunic acid, madasiatic acid and madecassic acid are secondary metabolites found in Centella asiatica. Both of these compounds have not been widely explored for their usefulness as a therapy for allergic asthma or as JAK3 inhibitors but are postulated to have anti-inflammatory effects and are beneficial for wound healing^16,47. Further evaluation of these two compounds is promising to explore their potential as novel and selective JAK3 inhibitors. Lupeol, a pentacyclic triterpene, is an active compound that is widely explored because of its broad spectrum of activity, including anti-inflammatory^48,49. In allergic asthma, an in vivo study in mice showed that lupeol reduced allergic inflammation of the airways⁴⁸. These positive findings certainly strengthen the results of our study in which lupeol has the potential to be developed as a complementary therapy for allergic asthma where the activity may be elicited through interaction with the JAK3 protein.

 

CONCLUSION:

In summary, our present in silico studies successfully explored several secondary metabolites of various medicinal plants with the potential to be developed as novel and selective JAK1 inhibitors or JAK3 inhibitors. However, further confirmation is needed to strengthen our findings through in vitro evaluation, in vivo effectiveness and toxicity tests, and clinical trials before their widespread application.

 

CONFLICT OF INTEREST:

The authors declare that there is no conflict of interes regarding this study.

 

ACKNOWLEDGMENTS:

The authors would like to thank Department of Pharmacy Practice, Faculty of Pharmacy, Universitas Airlangga for all support during this study.

 

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Accepted on 07.02.2022           © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(3):1167-1174.