Virtual Screening of Coffea arabica Phytochemicals as Natural β-Lactamase Inhibitors
DOI:
https://doi.org/10.53560/PPASB(62-3)1112Keywords:
Antibiotic Resistance, ADMET, β-lactamase Inhibitors, In-silico Modeling, Phytochemicals, Coffea arabicaAbstract
One of the key contributors to antimicrobial resistance is the enzymatic hydrolysis of β-lactam antibiotics by β-lactamases, becoming one of the leading public health challenges. In order to overcome this issue, the current work utilizes advanced in-silico grid-based molecular docking and post-docking analysis to identify potential β-lactamase inhibitors from Coffea arabica beans. Based on past experimental evidence of coffee’s antimicrobial activity, this research aimed to explore the inhibitory potential of its bioactive compounds through computational modeling to identify natural alternatives to synthetic inhibitors. Seventy-three phytochemicals were then screened and molecularly docked by AutoDock against four clinically relevant β-lactamases, namely, AmpC, CTX-M9, CTX-M14, and SHV-1, and subsequently subjected to toxicity and ADMET analysis. Among these, tannin, epicatechin, quercitrin, and quercetin exhibited the highest binding affinities (-8.5 kcal/mol, -7.7 kcal/mol, -8.6 kcal/mol, and -8.6 kcal/mol, respectively), outperforming the reference inhibitor, Avibactam. ADMET analysis also revealed favorable pharmacokinetic, low toxicity, and oral bioavailability of the top-ranked phytocompounds. Collectively, the results indicate the novelty of C. arabica’s phytochemicals as promising natural β-lactamase inhibitors. However, further in-vitro and in-vivo studies are required for validating their therapeutic efficacy against resistant bacteria. The current study also establishes a framework for integrating computational approaches in phytochemical research to accelerate antibacterial drug discovery.
References
1. I.N. Okeke, M.E.A. de Kraker, T.P. Van Boeckel, C.K. Kumar, H. Schmitt, A.C. Gales, S. Bertagnolio, M. Sharland, and R. Laxminarayan. The scope of the antimicrobial resistance challenge. The Lancet 403(10442): 2426-2438 (2024).
2. C.S. Ho, C.T.H. Wong, T.T. Aung, R. Lakshminarayanan, J.S. Mehta, S. Rauz, A. McNally, B. Kintses, S.J. Peacock, C. de la Fuente-Nunez, R.E.W. Hancock, and D.S.J. Ting. Antimicrobial resistance: a concise update. The Lancet Microbe 6(1): 100947 (2025).
3. M.S. Aljohni, M. Harun-Ur-Rashid, and S. Selim. Emerging threats: Antimicrobial resistance in extended-spectrum beta-lactamase and carbapenem-resistant Escherichia coli. Microbial Pathogenesis 200: 107275 (2025).
4. W.R. Miller and C.A. Arias. ESKAPE pathogens: antimicrobial resistance, epidemiology, clinical impact and therapeutics. Nature Reviews Microbiology 22(10): 598-616 (2024).
5. K. Singh, J.K. Gupta, D.K. Chanchal, M.G. Shinde, S. Kumar, D. Jain, Z.M. Almarhoon, A.M. Alshahrani, D. Calina, J. Sharifi-Rad, and A. Tripathi. Natural products as drug leads: exploring their potential in drug discovery and development. Naunyn-Schmiedeberg's Archives of Pharmacology 398(5): 4673-4687 (2025).
6. N. Chaachouay and L. Zidane. Plant-derived natural products: A source for drug discovery and development. Drugs and Drug Candidates 3(1): 184-207 (2024).
7. N. Chaachouay. Synergy, additive effects, and antagonism of drugs with plant bioactive compounds. Drugs and Drug Candidates 4(1): 43-54 (2025).
8. M.C. Ogwu, S.C. Izah, and M.T. Joshua. Ecological and environmental determinants of phytochemical variability in forest trees. Phytochemistry Reviews 3: 5-12 (2025).
9. B. Kongkham, A. Yadav, M.D. Ojha, D. Prabakaran, and P. Hariprasad In vitro and computational studies of the β-lactamase inhibition and β-lactam potentiating properties of plant secondary metabolites. Journal of Biomolecular Structure and Dynamics 41(20): 10326-10346 (2023).
10. M. Zubair. Antimicrobial and anti-biofilm activities of Coffea arabica L. against the clinical strains isolated from diabetic foot ulcers. Cureus 16(1): e52539 (2024).
11. E. Yohannis, T.A. Teka, J.A. Adebo, M.M. Urugo, A. Hossain, and T. Astatkie. Phytochemical constituents, ethnomedicinal uses, and applications of coffee (Coffea arabica) leaves in functional beverages. Journal of Food Composition and Analysis 135: 106570 (2024).
12. R. Castro-Díaz, N.P. Silva-Beltrán, N. Gámez-Meza, and K. Calderón. The antimicrobial effects of coffee and by-products and their potential applications in healthcare and agricultural sectors: A state-of-art review. Microorganisms 13(2): 215-226 (2025).
13. A. García-Gurrola, A.L. Martínez, A. Wall-Medrano, F.J. Olivas-Aguirre, E. Ochoa-Ruiz, and A.A. Escobar-Puentes. Phytochemistry, anti-cancer, and anti-diabetic properties of plant-based foods from Mexican agrobiodiversity: A review. Foods 13(24): 4176 (2024).
14. N. Macesic, A.-C. Uhlemann, and A.Y. Peleg. Multidrug-resistant Gram-negative bacterial infections. The Lancet 405(10474): 257-272 (2025).
15. Q. Yu, C. Wang, X. Zhang, H. Chen, M.X. Wu, and M. Lu. Photochemical strategies toward precision targeting against multidrug-resistant bacterial infections. ACS Nano 18(22): 14085-14122 (2024).
16. S. Abass, R. Parveen, M. Irfan, Z. Malik, S.A. Husain, and S. Ahmad. Mechanism of antibacterial phytoconstituents: an updated review. Archives of Microbiology 206(7): 325-332 (2024).
17. A. Choudhury. Potential role of bioactive phytochemicals in combination therapies against antimicrobial activity. Journal of Pharmacopuncture 25(2): 79-87 (2022).
18. P. Chihomvu, A. Ganesan, S. Gibbons, K. Woollard, and M.A. Hayes. Phytochemicals in drug discovery—A confluence of tradition and innovation. International Journal of Molecular Sciences 25(16): 8792 (2024).
19. P. Parida, S. Bhowmick, A. Saha, and M.A. Islam. Insight into the screening of potential beta-lactamase inhibitors as anti-bacterial chemical agents through pharmacoinformatics study. Journal of Biomolecular Structure and Dynamics 39(3): 923-942 (2021).
20. N.P. Dalbanjan and S.K.P. Kumar. A chronicle review of in-silico approaches for discovering novel antimicrobial agents to combat antimicrobial resistance. Indian Journal of Microbiology 64(3): 879-893 (2024).
21. O. Trott and A.J. Olson. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry 31(2): 455-461 (2010).
22. A. Ali, H.F. Zahid, J.J. Cottrell, and F.R. Dunshea. A comparative study for nutritional and phytochemical profiling of Coffea arabica (C. arabica) from different origins and their antioxidant potential and molecular docking. Molecules 27(16): 5126 (2022).
23. Y. Jabeen, N. Ansari, H. Rasheed, M.A. Rasheed, M. Awais, M. Ibrahim, S. Kanwal, A. Khalid, M.A. Zahid, and F. Jamil. Let's dock: A smart platform for molecular docking. Pakistan Journal of Zoology 54(4): 1577-1582 (2022).
24. M. Castanheira, P.J. Simner, and P.A. Bradford. Extended-spectrum β-lactamases: an update on their characteristics, epidemiology and detection. JAC-Antimicrobial Resistance 3(3): dlab092 (2021).
25. M.K. Rahman, H. Rodriguez-Mori, G. Loneragan, and B. Awosile. One Health distribution of beta-lactamases in Enterobacterales in the United States: A systematic review and meta-analysis. International Journal of Antimicrobial Agents 65(2): 107422 (2025).
26. S. Tang, R. Chen, M. Lin, Q. Lin, Y. Zhu, J. Ding, H. Hu, M. Ling, and J. Wu. Accelerating autodock vina with gpus. Molecules 27(9): 3041-3046 (2022).
27. S.S. Butt, Y. Badshah, M. Shabbir, and M. Rafiq. Molecular docking using chimera and autodock vina software for nonbioinformaticians. JMIR Bioinformatic and Biotechnology 1(1): e14232 (2020).
28. M.A. Rauf, S. Zubair, and A. Azhar. Ligand docking and binding site analysis with pymol and autodock/vina. International Journal of Applied Sciences 4(2): 168-174 (2015).
29. D. Seeliger and B.L. de Groot. Ligand docking and binding site analysis with PyMOL and Autodock/Vina. Journal of Computer Aided Molecular Design 24(5): 417-422 (2010).
30. A.R. Yadav and S.K. Mohite. ADME analysis of phytochemical constituents of Psidium guajava. Indian Journal of Phytochemistry 13(5): 373-375 (2020).
31. C. Grosso, M. Santos, and M.F. Barroso. From plants to psycho-neurology: unravelling the therapeutic benefits of bioactive compounds in brain disorders. Antioxidants 12(8): 1603-1610 (2023).
32. K. Li, Y. Du, L. Li, and D.-Q. Wei. Bioinformatics approaches for anti-cancer drug discovery. Current Drug Targets 21(1): 3-17 (2020).
33. N. Berdigaliyev and M. Aljofan. An overview of drug discovery and development. Future Medicinal Chemistry 12(10): 939-947 (2020).
34. S. Motta, M. Guaita, C. Cassino, and A. Bosso. Relationship between polyphenolic content, antioxidant properties and oxygen consumption rate of different tannins in a model wine solution. Food Chemistry 313: 126045 (2020).
35. W. Zhang, Z.-Y. Yang, X.-W. Cheng, R.-C. Tang, and Y.-F. Qiao. Adsorption, antibacterial and antioxidant properties of tannic acid on silk fiber. Polymers 11(6): 970-976 (2019).
36. L.F.M. de Melo, V.G. de Queiroz Aquino-Martins, A.P. da Silva, H.A.O. Rocha, and K.C. Scortecci. Biological and pharmacological aspects of tannins and potential biotechnological applications. Food Chemistry 414: 135645 (2023).
37. A.M. Somboro, J.O. Sekyere, D.G. Amoako, H.M. Kumalo, R. Khan, L.A. Bester, and S.Y. Essack. In vitro potentiation of carbapenems with tannic acid against carbapenemase-producing enterobacteriaceae: exploring natural products as potential carbapenemase inhibitors. Journal of Applied Microbiology 126(2): 452-467 (2019).
38. A. Stavitskaya, C. Shakhbazova, Y. Cherednichenko, L. Nigamatzyanova, G. Fakhrullina, N. Khaertdinov, G. Kuralbayeva, A. Filimonova, V. Vinokurov, and R. Fakhrullin. Antibacterial properties and in vivo studies of tannic acid-stabilized silver–halloysite nanomaterials. Clay Minerals 55(2): 112-119 (2020).
39. A. Konputtar, W. Aengwanich, B. Saraphol, and M. Yossapol. Antimicrobial activity of polyphenols extracted from Thai medical plants on extended-spectrum beta-lactamase-producing Escherichia coli isolates from healthy dairy cows. Polish Journal of Veterinary Sciences 25(4): 501-510 (2022).
40. A. Vafadar, Z. Shabaninejad, A. Movahedpour, F. Fallahi, M. Taghavipour, Y. Ghasemi, M. Akbari, A. Shafiee, S. Hajighadimi, S. Moradizarmehri, E. Razi, A. Savardashtaki, and H. Mirzaei. Quercetin and cancer: new insights into its therapeutic effects on ovarian cancer cells. Cell and Bioscience 10: 32-39 (2020).
41. H.S. Semis, C. Gur, M. Ileriturk, F.M. Kandemir, and O. Kaynar. Evaluation of therapeutic effects of quercetin against Achilles tendinopathy in rats via oxidative stress, inflammation, apoptosis, autophagy, and metalloproteinases. The American Journal of Sports Medicine 50(2): 486-498 (2022).
42. F. Di Pierro, G. Derosa, P. Maffioli, A. Bertuccioli, S. Togni, A. Riva, P. Allegrini, A. Khan, S. Khan, and B.A. Khan. Possible therapeutic effects of adjuvant quercetin supplementation against early-stage COVID-19 infection: a prospective, randomized, controlled, and open-label study. International Journal of General Medicine 14: 2359-2366 (2021).
43. X. Jian, C. Shi, W. Luo, L. Zhou, L. Jiang, and K. Liu. Therapeutic effects and molecular mechanisms of quercetin in gynecological disorders. Biomedicinal Pharmacotherapy 173: 116418-116424 (2024).
44. H. Seo, S.-H. Lee, Y. Park, H.-S. Lee, J.S. Hong, C.Y. Lim, D.H. Kim, S.-S. Park, H.J. Suh, and K.-B. Hong. (−)-Epicatechin-enriched extract from Camellia sinensis improves regulation of muscle mass and function: Results from a randomized controlled trial. Antioxidants 10(7): 1026-1031 (2021).
45. Z. Wang, Z. Lu, Y. Chen, C. Wang, P. Gong, R. Jiang, and Q. Liu. Targeting the AKT‐P53/CREB pathway with epicatechin for improved prognosis of traumatic brain injury. CNS Neuroscience and Therapeutics 30(2): e14364 (2024).
46. Z. Qu, A. Liu, P. Li, C. Liu, W. Xiao, J. Huang, Z. Liu, and S. Zhang. Advances in physiological functions and mechanisms of (−)-epicatechin. Critical Reviews in Food Science and Nutrition 61(2): 211-233 (2021).
47. D. Buchmann, N. Schultze, J. Borchardt, I. Böttcher, K. Schaufler, and S. Guenther. Synergistic antimicrobial activities of epigallocatechin gallate, myricetin, daidzein, gallic acid, epicatechin, 3‐hydroxy‐6‐methoxyflavone and genistein combined with antibiotics against ESKAPE pathogens. Journal of Applied Microbiology 132(2): 949-963 (2022).
48. F. Teng, L. Wang, J. Wen, Z. Tian, G. Wang, and L. Peng. Epicatechin gallate and its analogues interact with sortase A and β-lactamase to suppress Staphylococcus aureus virulence. Frontiers in Cellular and Infection Microbiology 15: 1-15 (2025).
49. W. Wang, X. Ren, Y. Bao, Y. Zhu, Y. Zhang, J. Li, and Z. Peng. Inhibitory effects of hyperoside and quercitrin from Zanthoxylum bungeanum Maxim. leaf on 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine formation by trapping phenylacetaldehyde. European Food Research and Technology 248: 25-34 (2022).
50. P. Sophiya, D. Urs, J. K Lone, A. Giresha, H. Krishna Ram, J. G Manjunatha, H.A. El-Serehy , M. Narayanappa, J. Shankar, R. Bhardwaj, S. Ahmad Guru, and K. K Dharmappa. Quercitrin neutralizes sPLA2IIa activity, reduces the inflammatory IL-6 level in PC3 cell lines, and exhibits anti-tumor activity in the EAC-bearing mice model. Frontiers in Pharmacology 13: 996285 (2022).
51. B.F. Mirto, L. Scafuri, E. Sicignano, C.D. Luca, P. Angellotto, G.D. Lorenzo, D. Terracciano, C. Buonerba, and A. Falcone. Nature’s hidden gem: quercitrin’s promising role in preventing prostate and bladder cancer. Future Science OA 9(6): FSO867 (2023).
52. D.Y. Li, L.X. Yue, S.G. Wang, and T.X. Wang. Quercitrin restrains the growth and invasion of lung adenocarcinoma cells by regulating gap junction protein beta 2. Bioengineered 13(3): 6126-6135 (2022).
53. J. Kim, S.R. Kim, Y.-H. Choi, J.Y. Shin, C.D. Kim, N.-G. Kang, B.C. Park, and S. Lee. Quercitrin stimulates hair growth with enhanced expression of growth factors via activation of MAPK/CREB signaling pathway. Molecules 25(17): 4004-4011 (2020).
54. T.K. Karami, S. Hailu, S. Feng, R. Graham, and H.J. Gukasyan. Eyes on Lipinski's rule of five: A New “rule of thumb” for physicochemical design space of ophthalmic drugs. Journal of Ocular Pharmacology and Therapeutics 38(1): 43-55 (2022).
55. V. Ivanović, M. Rančić, B. Arsić, and A. Pavlović. Lipinski’s rule of five, famous extensions and famous exceptions. Chemia Naissensis 3(1): 171-177 (2020).
56. P. Rani, B.K. Rajak, and D.V. Singh. Physicochemical parameters for design and development of lead herbicide molecules: Is ‘Lipinski's rule of 5′ appropriate for herbicide discovery? Pest Management Science 79(5): 1931-1943 (2023).
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