Chronic Obstructive Pulmonary Disease (COPD) is one of the complex progressive disorders that affect the respiratory system [1] and causes chronic inflammation of the airways [2]. COPD is accountable for more than 3 million deaths annually, making it the third leading cause of mortality [3]. There are several causes for COPD, which provoke the Endoplasmic Reticulum (ER) stress including smoking, free radicals, carcinogens, and reactive oxygen species [4]. Since ER strives to reimpose the cellular homeostasis through unfolded protein response (UPR), it is evident that ER stress and UPR activation occur in patients with COPD [5]. The other major cause for COPD is breathing of polluted air and also the result of subjection to inhaled irritants [1, 6]. COPD is frequently associated with non-small cell lung cancer (comorbidity) [7]. Factors such as age, bacterial colonization, cardiovascular diseases, usage of antibiotics and steroids, poor quality of life, and airway obstruction severity intensify the risk for COPD [8, 9]. One of the uncharacterized risk factors of COPD is the longtime occupational exposure to irritants like organic and inorganic dust, chemical agents, and fumes [1]. These risk factors are being changed over time with new forms of smoking and also the location with the difference in air pollution [10]. COPD is commonly accompanied by exacerbations, which are marked with increased cough, excess sputum production, and phlegm [11]. It is deemed that among the exacerbations, 70–80% are prompted by bacterial or viral respiratory infections and the remaining 20–30% are due to environmental pollution exposure or unknown causation or origination [12]. In general, COPD is an escalating disease of the airways, the microvasculature, and the alveoli and is strongly associated with cardiovascular diseases [13]. Although COPD represents an increased burden to the Healthcare system, it is not easy to diagnose and curate the disease due to its heterogenicity and complexity. Currently, this disease is treated by both Pharmacological and non-pharmacological approaches. The pharmacological intervention includes inhaled bronchodilators, antibiotics, corticosteroids, Oxygen therapy, and antioxidants. Based on the clinical conditions of the patient, adjunct therapies are also performed. Non-pharmacological intervention includes Chest percussion therapy, which is believed to improve sputum clearance. Ventilatory support should be the primary goal to reduce morbidity and mortality [12]. Currently, the prognosis of COPD is achieved by post-bronchodilator spirometry and by Pulse oximetry [1].

The Indian medical system is one of the ancient traditional health care systems in the globe and this system is predominantly based on herbal plants. Thus, repurposing Indian traditional practices can be employed in mining new options to treat deadly diseases. Among numerous plants mentioned in the Indian medical system, Vitex negundo L. commonly known as Nirgundi belongs to the family Lamiaceae [14] is one of the significant plants that was being used in the treatment for various disorders.

The plant contains various bioactive compounds extracted and concentrated from roots, leaves, and seeds in the form of iridoids, terpenes, volatile oils, lignans, steroids, and flavonoids. These different bioactive compounds exhibit various pharmacological properties including anti-inflammatory, antimicrobial, antioxidant, anti-ulcer, anti-diabetic properties, hepatoprotective properties [15]. The leaves have been used as a sedative, vermifuge, astringent, tonic, febrifuge, and also used in imparting the joint swellings from Acute Rheumatism. The dried fruit can be used as a Quinacrine and is used in the treatment of cough, cold, heart diseases, coronary thrombosis, rheumatic difficulties, etc. [16]. Jianpiyifei II granules (JPYF II) is one of the herbal medications used for COPD in China which comprises V. negundo L. is an important component [5, 15]. Since we have a limited number of drugs and disease-modifying therapies to treat COPD, the unraveling of the genetic determinants of COPD provides the unbiased identification of molecular determinants which would pave the way to derive new insights into the pathogenesis of COPD leading to novel therapeutic interventions and preventive strategies.

Despite the significance of the Indian traditional treatment system, the functions of phytocompounds, their potential human targets, and their mode of actions are still indistinct. Several studies have shown the specific activity of these compounds, but the mode of action and multiple potentialities of these compounds are yet to be fully discovered. Hence, the present study aims to highlight the advances in the discovery of druggable targets of phytomolecules in association with COPD through systems pharmacology, cheminformatics, and molecular docking approaches. This study tries to address the primary queries regarding:

(i) The regulatory aspects of phytocompounds against COPD.

(ii) The biological processes mediated by plant molecules through human targets.

Cheminformatics approach was employed to segregate the phytochemicals with significant curative properties through target-compound interactions and molecular docking was performed to evaluate the interactions. The derived COPD immunological receptors were analyzed using bioinformatic databases to identify the pathways and mechanisms in which the bioactive compounds act. So, it is expected that these in silico systems approaches can aid in the investigation of the immunological significance of V. negundo L. derived specialized molecules and will significantly promote the development of new drugs for the treatment of COPD and other respiratory diseases in mere future.

COPD is a systemic disorder [23] that involves structural alterations in both lung parenchyma and respiratory airways [24], which requires intensive research for the development of proper treatment methods. Since the allopathic formulations are not effective at present, exploration of alternative solutions has become necessary. More than 50% of the world’s population has started the usage of alternative medicines, where the Indian ancient medicinal knowledge become highly significant [25]. India had a well-established ayurvedic system since ancient times [26], with more than 1500 well-studied plants are officially incorporated in ayurvedic formulations [27]. But the exact mode and mechanism of these medicinal plants remain unknown [26]. Hence, in this study, we have integrated the pharmacology, cheminformatics, and molecular docking approaches to identify the highly potent compounds present in V. negundo L. and to reveal its mode of action in treating COPD at the molecular level.

In this investigation, 86 bio-active molecules were identified with the help of cheminformatics. All these 86 molecules have strong interactions with more than 1300 human targets directly. These compounds have been hypothesized to be involved in various molecular and biological processes against COPD. Followingly, Cytoscape 3.8.2 was used to obtain the molecular interactions and C-T-N. These results predict the mechanism of drug compounds involved in various biological processes to achieve therapeutic potential.

As highlighted by previous reports, the binding of compounds to only a single direct target does not yield relevant results [28]. From a network point of view, the receptors or genes that are needed to be targeted have shifted from unique proteins to a whole molecular network of genes involved in causing disease [29]. These multiple interactions of drugs with various targets increase the efficiency of the drugs and the probability of effective treatment [26]. Results from Swiss target prediction and C-T-N have shown that each potential compound can act on multiple targets, that are involved in the development of COPD. Since various gene regulations are intricated in causing COPD, multi-target effects of these compounds can be used to achieve superior results.

Subsequently, molecular docking analysis was performed to verify the potentials of these compounds. Results of docking display the significant binding energies between the plant compounds and the respective human targets. The genes AAT and IREB2 play a significant role in causing lung inflammation [30, 31] genes CHRNA3 and CHRNA 5 play a crucial role in lung cancer development [32], and genes MMP12, SOX5, and TGFB1 involve in the prognosis of emphysema [33, 34, 35]. These medical conditions namely lung inflammation, lung cancer, and emphysema are the hallmarks of COPD and these seven genes can be regarded as candidate genes for COPD. Targeting these genes will pave way for the treatment of COPD. Hence, molecular docking was performed against these candidate gene products. Among the phytocompounds, CD interacts with the highest binding affinities of –7.5 and –6.8 kcal/mol with IREB2 and AAT respectively. In general, CD exhibits the highest affinity with almost all the seven targets followed by CPE, CPO, and EL. These results revealed that V. negundo L. compounds possess significant regulatory actions on COPD target receptors through dynamic interactions.

Finally, highly potent molecules were identified by comparing the properties of phytocompounds with commercially available drugs, which shows the curative potential of V. negundo L. and also the proof for the Indian medical system as a highly potent approach for treating diseases, when modern treatment methods cannot yield desired outcomes.

In brief, among the 1300 genes targeted by phytocompounds present in V. negundo L., seven targets were predicted to be responsible for causing COPD using the combined analyses. Among 86 phytocompounds, four compounds were predicted to be highly potent phytocompounds, which can be employed for treating COPD after laboratory trials and validation.

The present study revealed that the V. negundo L. showed diverse immune–stimulants to treat the airflow obstruction and enhance the breathing capabilities of COPD cases. Biopharmaceutical research on V. negundo L. is still a bottleneck, interestingly our results on potentially specialized molecules and their pharmacological features, active human targets, enrichment analyses, and signaling networks have enabled the floodgates of research with the integration of Ayurveda to the era of modern medicine. This is the first investigation that identified the pivotal aspects of host immune responses to COPD. This study also conjectures that V. negundo L. phytomolecules and their combination with other biomolecules as is recommended by the Ayurvedic and modern medicine system—may result in combined effects and further studies are required.

Hence, we hypothesize that the identified potential compounds from this herb can be used to regulate the gene-targeted pathways, which can ultimately result in the cure of COPD. Yet, in vivo evaluation is required to further validate this hypothesis. Furthermore, it is suggested that obtained interaction can be useful to design competitive human immune targets antagonist which will pave the way to combat COPD.

COPD, Chronic Obstructive Pulmonary Disease; ER, Endoplasmic Reticulum; GO, Gene Ontology; C-T-N, Compound-Target-Network; nVio, Number of Violations; GPCR, GPCR Ligand Activity; Ncr, Enzymes, and Nuclear Receptors; Ki, Kinase Activity; Ei, Enzyme Inhibition Activity; Pi, Protease Inhibitory Activity.

Conceptualization—SA, PM and MR; Data curation—RJ, and MAL; Investigation—SA, PM, RJ, MAL and SKP; Supervision—J-TC, MR; Validation—RS, HS, and J-TC; Writing - original draft—SA and PM; Writing - review & editing—RS, SKP, HS, J-TC, and MR. All authors have read and agreed to the published version of the manuscript.

Not applicable.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.