With increasing environmental pollution (rising levels of air borne allergens) and smoke inhalational habits, biomass smoke, etc. all affect lung health, leading to various chronic lung diseases, and among them, life-threatening chronic obstructive pulmonary disease (COPD) is growing in prevalence around the globe. Thus, it’s a great demand from researchers to discover novel therapeutic drugs and vaccines against COPD. Human neutrophil elastase (HNE) is a major inflammatory protein that triggers inflammation in chronic airway diseases, causing airway remodeling and cytokines release. Recently, it has emerged as a significant target for drug discovery in patients with COPD. Hence, this study aimed to investigate the In-silico screening of the phytochemical medicinal plant Tridax procumbens against COPD via targeting HNE using the Schrodinger suite 2023-1. The docking score, glide score, and binding energy were calculated by the glide program using the Prime MM-GB/SA (Molecular Mechanics with Generalized Born and Surface Area Solvation) module. The best selected phytochemicals (ligands) were then screened for pharmacokinetic properties via ADMET analysis predicted using the qikProp program. Out of the library of Tridax procumbens, the phytochemicals like Apigetrin, Puerarin, Centaureidin, and Myricetin significantly bind to the catalytic site of HNE with PHE41, CYS42, SER195, GLY193, PHE192, HIS57, CYS58, PHE215, SER214, ASN61, LEU998, PRO98, TYR94, and ASP95 as residues with a glide score of the highest binding affinity (−7.707, −7.707, −7.045, and −6.871, respectively) compared to the standard drugs; Dexamethasone (−4.964), Roflumilast (−4.833), and Fluticasone (−3.968). The ADMET analysis of these four phytochemicals showed good pharmacokinetic profiles with human oral absorption, log S, molar volume, and van der waals volume, etc. Thus, In-silico findings suggest that carrying out these phytochemicals (Apigetrin, Puerarin, Centaureidin, and Myricetin) from Tridax procumbens to validate their therapeutic potential against COPD at preclinical and clinical levels.

1. Singh D, Agusti A, Anzueto A, et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: the GOLD science committee report 2019. European Respiratory Journal. 2019; 53(5): 1900164. doi: 10.1183/13993003.00164-2019

2. Zhang MY, Jiang YX, Yang YC, et al. Cigarette smoke extract induces pyroptosis in human bronchial epithelial cells through the ROS/NLRP3/caspase-1 pathway. Life Sciences. 2021; 269: 119090. doi: 10.1016/j.lfs.2021.119090

3. Hansen G, Gielen-Haertwig H, Reinemer P, et al. Unexpected Active-Site Flexibility in the Structure of Human Neutrophil Elastase in Complex with a New Dihydropyrimidone Inhibitor. Journal of Molecular Biology. 2011; 409(5): 681-691. doi: 10.1016/j.jmb.2011.04.047

4. Abboud RT, Vimalanathan S. Pathogenesis of COPD. Part I. The role of protease-antiprotease imbalance in emphysema, 2008.

5. Kulkarni T, O’Reilly P, Antony VB, et al. Matrix Remodeling in Pulmonary Fibrosis and Emphysema. American Journal of Respiratory Cell and Molecular Biology. 2016; 54(6): 751-760. doi: 10.1165/rcmb.2015-0166ps

6. Gadek JE, Fells GA, Zimmerman RL, et al. Antielastases of the human alveolar structures. Implications for the protease-antiprotease theory of emphysema. Journal of Clinical Investigation. 1981; 68(4): 889-898. doi: 10.1172/jci110344

7. Wang Z, Chen F, Zhai R, et al. Plasma Neutrophil Elastase and Elafin Imbalance Is Associated with Acute Respiratory Distress Syndrome (ARDS) Development. PLoS ONE. 2009; 4(2): e4380. doi: 10.1371/journal.pone.0004380

8. Voynow J, Fischer B, Zheng S. Proteases and cystic fibrosis. The International Journal of Biochemistry & Cell Biology. 2008; 40(6-7): 1238-1245. doi: 10.1016/j.biocel.2008.03.003

9. Hofman PM. Pathobiology of the neutrophil-intestinal epithelial cell interaction: Role in carcinogenesis. World Journal of Gastroenterology. 2010; 16(46): 5790. doi: 10.3748/wjg.v16.i46.5790

10. Inoue Y, Omodani T, Shiratake R, et al. Development of a highly water-soluble peptide-based human neutrophil elastase inhibitor; AE-3763 for treatment of acute organ injury. Bioorganic & Medicinal Chemistry. 2009; 17(21): 7477-7486. doi: 10.1016/j.bmc.2009.09.020

11. Wang C, Zhou J, Wang J, et al. Progress in the mechanism and targeted drug therapy for COPD. Signal Transduction and Targeted Therapy. 2020; 5(1). doi: 10.1038/s41392-020-00345-x

12. Yip E, Karimi S, T. Pien L. Evaluation of a Therapeutic Interchange from Fluticasone/Salmeterol to Mometasone/Formoterol in Patients with Chronic Obstructive Pulmonary Disease. Journal of Managed Care & Specialty Pharmacy. 2016; 22(4): 316-323. doi: 10.18553/jmcp.2016.22.4.316

13. Babu KS, Morjaria JB. Umeclidinium in chronic obstructive pulmonary disease: latest evidence and place in therapy. Therapeutic Advances in Chronic Disease. 2017; 8(4-5): 81-91. doi: 10.1177/2040622317700822

14. Quint JK, Ariel A, Barnes PJ. Rational use of inhaled corticosteroids for the treatment of COPD. npj Primary Care Respiratory Medicine. 2023; 33(1). doi: 10.1038/s41533-023-00347-6

15. Chaudhari HC, Patil KP, Mandal PSGVP. A Review on Medicinal Importance of Tridax Procumbens Linn. Research & Reviews in Pharmacy and Pharmaceutical Sciences. 2022.

16. Ingole VV, Mhaske PC, Katade SR. Phytochemistry and pharmacological aspects of Tridax procumbens (L.): A systematic and comprehensive review. Phytomedicine Plus. 2022; 2(1): 100199. doi: 10.1016/j.phyplu.2021.100199

17. Kalirajan R, Muralidharan V, Jubie S, et al. Microwave assisted synthesis, characterization and evaluation for their antimicrobial activities of some novel pyrazole substituted 9-anilino acridine derivatives. International Journal of Health & Allied Sciences. 2013; 2(2): 81. doi: 10.4103/2278-344x.115682

18. Grace VMB, Viswanathan S, Wilson DD, et al. Significant action of Tridax procumbens L. leaf extract on reducing the TNF-α and COX-2 gene expressions in induced inflammation site in Swiss albino mice. Inflammopharmacology. 2019; 28(4): 929-938. doi: 10.1007/s10787-019-00634-0

19. Gálvez J, Polo S, Insuasty B, et al. Design, facile synthesis, and evaluation of novel spiro- and pyrazolo[1,5-c]quinazolines as cholinesterase inhibitors: Molecular docking and MM/GBSA studies. Computational Biology and Chemistry. 2018; 74: 218-229. doi: 10.1016/j.compbiolchem.2018.03.001

20. Rani S, Ansari MN, Saeedan AS, Kaithwas G . Novel Quinazoline Derivative Activates FIH-1 in MCF-7 Cells and 7, 12-Dimethylbenz[a]-Anthracene Induced Mammary Gland Carcinoma in Albino Rats. J Biol Regul Homeost Agents. 2024; 38(5). doi: 10.23812/j.biol.regul.homeost.agents.20243805.330

21. Kalirajan R, Muralidharan V, Jubie S, et al. Synthesis of Some Novel Pyrazole‐Substituted 9‐Anilinoacridine Derivatives and Evaluation for their Antioxidant and Cytotoxic Activities. Journal of Heterocyclic Chemistry. 2012; 49(4): 748-754. doi: 10.1002/jhet.848

22. Roos K, Wu C, Damm W, et al. OPLS3e: Extending Force Field Coverage for Drug-Like Small Molecules. Journal of Chemical Theory and Computation. 2019; 15(3): 1863-1874. doi: 10.1021/acs.jctc.8b01026

23. Jacobson MP, Pincus DL, Rapp CS, et al. A hierarchical approach to all‐atom protein loop prediction. Proteins: Structure, Function, and Bioinformatics. 2004; 55(2): 351-367. doi: 10.1002/prot.10613

24. Barros RO, Junior FLCC, Pereira WS, et al. Interaction of Drug Candidates with Various SARS-CoV-2 Receptors: An in Silico Study to Combat COVID-19. Journal of Proteome Research. 2020; 19(11): 4567-4575. doi: 10.1021/acs.jproteome.0c00327

25. Naresh P, Selvaraj A, Shyam SP, et al. Targeting a conserved pocket (n-octyl-β-D-glucoside) on the dengue virus envelope protein by small bioactive molecule inhibitors. Journal of Biomolecular Structure and Dynamics. 2020; 40(11): 4866-4878. doi: 10.1080/07391102.2020.1862707

26. Li J, Abel R, Zhu K, et al. The VSGB 2.0 model: A next generation energy model for high resolution protein structure modeling. Proteins: Structure, Function, and Bioinformatics. 2011; 79(10): 2794-2812. doi: 10.1002/prot.23106