Antibacterial Potential of Ximenia americana L. Olacaceae: Molecular Docking, Molecular Dynamics, and ADMET Prediction
DOI:
https://doi.org/10.31436/jop.v4i1.252Keywords:
ADMET, molecular docking, Molecular dynamics, Stigmasterol, Ximenia americanaAbstract
Introduction: The devastating effect of persistent and recurrent bacterial infections coupled with antibiotic resistance is a driving force for prospects into alternative antibacterial therapeutics to achieve treatment. This study investigates the antibacterial potential of Ximenia americana (XA) via molecular docking, molecular dynamics, and ADMET approach.
Materials and methods: The ligands and target were downloaded from respective databases and docked using PyRx software followed by molecular dynamics simulation (MDS) with iMOD and CABflex 2.0 online servers then ADMET, drug likeness, lead likeness, and medicinal chemistry predictions of the top docked ligands using pkCSM and SwissADME online servers.
Results: Stigmasterol exhibited the lowest binding affinity and inhibition constant respectively with all the targets; enoyl-acyl-carrier-protein reductase (-7.1 kcal/mol and 6.16 µM), Penicillin-binding Protein 2X (-8.8 kcal/mol and 0.35 µM), dihydrofolate reductase (-9.6 kcal/mol and 0.09 µM), dihydropteroate Synthase (-7.8 kcal/mol and 1.89 µM), UDP-N-acetylglucosamine enolpyruvyl transferase (-7.1 kcal/mol and 6.16 µM), and topoisomerase IV (-7.8 kcal/mol and 1.89 µM). The MDS showed several cluster displacements and residue fluctuations with the docked targets with higher residue fluctuations observed for enoyl-acyl-carrier-protein reductase (11.33 ?), Penicillin-binding Protein 2X (4.67 ?), dihydrofolate reductase (3.61 ?), dihydropteroate Synthase (4.97 ?), UDP-N-acetylglucosamine enolpyruvyl transferase (3.38 ?), and topoisomerase IV (4.35 ?). 4,4-Dimethylcyclohex-2-en-1-ol exhibited superior overall ADMET properties, oral bioavailability, drug-likeness, and medicinal chemistry.
Conclusion: Conclusively, Stigmasterol and 4,4-Dimethylcyclohex-2-en-1-ol might be responsible for the antibacterial effect of XA. Although the latter showed better interaction with the target proteins, the former showed better ADMET properties, oral bioavailability, drug-likeness, and medicinal properties. However, improvement in these properties might enhance their antibacterial activity.
References
Agustina, F., & Nugroho, R. P. P. (2021). Antibacterial Potential of Bidara Laut (Ximenia americana) Plant Against Vibrio alginolyticus and V. parahaemolyticus Bacteria. Bioeduscience, 5(1), 15-23.
Askari, S. B., & Krajinovic, M. (2010). Dihydrofolate reductase gene variations in susceptibility to disease and treatment outcomes. Current genomics, 11(8), 578-583.
Bakrim, W. B., Nurcahyanti, A. D. R., Dmirieh, M., Mahdi, I., Elgamal, A. M., El Raey, M. A., Wink, M., & Sobeh, M. (2022). Phytochemical profiling of the leaf extract of Ximenia americana var. Caffra and its antioxidant, antibacterial, and antiaging activities in vitro and in Caenorhabditis elegans: a cosmeceutical and dermatological approach. Oxidative Medicine and Cellular Longevity, 2022, 3486257.
Cao, H., Gao, M., Zhou, H., & Skolnick, J. (2018). The crystal structure of a tetrahydrofolate-bound dihydrofolate reductase reveals the origin of slow product release. Communications Biology, 1(1), 226. https://doi.org/10.1038/s42003-018-0236-y
Chassagne, F., Samarakoon, T., Porras, G., Lyles, J. T., Dettweiler, M., Marquez, L., Salam, A. M., Shabih, S., Farrokhi, D. R., & Quave, C. L. (2021). A Systematic Review of Plants With Antibacterial Activities: A Taxonomic and Phylogenetic Perspective [Systematic Review]. Frontiers in Pharmacology, 11, 2020. https://www.frontiersin.org/articles/10.3389/fphar.2020.586548
Clegg, L. E., & Mac Gabhann, F. (2015). Molecular mechanism matters: Benefits of mechanistic computational models for drug development. Pharmacological Research, 99, 149-154. https://doi.org/https://doi.org/10.1016/j.phrs.2015.06.002
Dahiru, M. M., Abaka, A. M., & Artimas, S. P. (2023a). Phytochemical Analysis and Antibacterial Activity of Methanol and Ethyl Acetate Extracts of Detarium microcarpum Guill. & Perr. Biology, Medicine, & Natural Product Chemistry, 12(1), 281-288.
Dahiru, M. M., Abaka, A. M., & Musa, N. (2023b). Phytochemical Analysis, In-vitro, and In-silico Antibacterial Activity of Stembark Extract of Anogeissus leiocarpus (DC) Guill and Perr. Sciences of Pharmacy, 2(3), 24-41.
Dahiru, M. M., Badgal, E. B., & Musa, N. (2022). Phytochemistry, GS-MS analysis, and heavy metals composition of aqueous and ethanol stem bark extracts of Ximenia americana. GSC Biological and Pharmaceutical Sciences, 21(3), 145-156.
Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7(1), 42717.
de Menezes, I. R. A., da Costa, R. H. S., Augusti Boligon, A., Rolón, M., Coronel, C., Vega, C., Melo Coutinho, H. D., da Costa, M. S., Tintino, S. R., Silva Pereira, R. L., de Albuquerque, T. R., da Silva Almeida, J. R. G., & Quintans-Júnior, L. J. (2019). Ximenia americana L. enhances the antibiotic activity and inhibit the development of kinetoplastid parasites. Comparative Immunology, Microbiology and Infectious Diseases, 64, 40-46. https://doi.org/https://doi.org/10.1016/j.cimid.2019.02.007
de Oliveira, M. V. D., Furtado, R. M., da Costa, K. S., Vakal, S., & Lima, A. H. (2022). Advances in UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA) Covalent Inhibition [Mini Review]. Frontiers in Molecular Biosciences, 9, 889825. https://www.frontiersin.org/articles/10.3389/fmolb.2022.889825
Doughari, J. H. (2012). Phytochemicals: extraction methods, basic structures and mode of action as potential chemotherapeutic agents. INTECH Open Access Publisher Rijeka, Croatia.
Ebbo, A. A., Sani, D., Suleiman, M. M., Ahmed, A., & Hassan, A. Z. (2019). Phytochemical Composition, Proximate Analysis and Antimicrobial Screening of the Methanolic Extract of Diospyros mespiliformis Hochst Ex a. Dc (Ebenaceae). Pharmacognosy Journal, 11(2), 362-368.
Gajdács, M., & Albericio, F. (2019). Antibiotic resistance: from the bench to patients. Antibiotics, 8(3), 129.
Griffith, E. C., Wallace, M. J., Wu, Y., Kumar, G., Gajewski, S., Jackson, P., Phelps, G. A., Zheng, Z., Rock, C. O., Lee, R. E., & White, S. W. (2018). The Structural and Functional Basis for Recurring Sulfa Drug Resistance Mutations in Staphylococcus aureus Dihydropteroate Synthase [Original Research]. Frontiers in Microbiology, 9, 1369. https://www.frontiersin.org/articles/10.3389/fmicb.2018.01369
Helgesen, E., Sætre, F., & Skarstad, K. (2021). Topoisomerase IV tracks behind the replication fork and the SeqA complex during DNA replication in Escherichia coli. Scientific Reports, 11(1), 474. https://doi.org/10.1038/s41598-020-80043-4
Hollingsworth, S. A., & Dror, R. O. (2018). Molecular dynamics simulation for all. Neuron, 99(6), 1129-1143.
Hooper, D. C., & Jacoby, G. A. (2016). Topoisomerase inhibitors: fluoroquinolone mechanisms of action and resistance. Cold Spring Harbor Perspectives in Medicine, 6(9), a025320.
Hopf, F. S. M., Roth, C. D., de Souza, E. V., Galina, L., Czeczot, A. M., Machado, P., Basso, L. A., & Bizarro, C. V. (2022). Bacterial Enoyl-Reductases: The Ever-Growing List of Fabs, Their Mechanisms and Inhibition [Review]. Frontiers in Microbiology, 13, 2020. https://www.frontiersin.org/articles/10.3389/fmicb.2022.891610
Hrast, M., Sosi?, I., Šink, R., & Gobec, S. (2014). Inhibitors of the peptidoglycan biosynthesis enzymes MurA-F. Bioorganic Chemistry, 55, 2-15. https://doi.org/https://doi.org/10.1016/j.bioorg.2014.03.008
Jendele, L., Krivák, R., Škoda, P., Novotný, M., & Hoksza, D. (2019). PrankWeb: a web server for ligand binding site prediction and visualization. Nucleic Acids Research, 47, 345-349. https://doi.org/10.1093/nar/gkz424
Kapoor, G., Saigal, S., & Elongavan, A. (2017). Action and resistance mechanisms of antibiotics: A guide for clinicians. Journal of Anaesthesiology, Clinical Pharmacology, 33(3), 300–305.
Kiessoun, K., Roland, M. N. T., Mamounata, D., Yomalan, K., Sytar, O., Souz, A., Brestic, M., & Dicko, M. H. (2018). Antimicrobial profiles, antidiarrheal and antipyretic capacities of phenol acid rich-fractions from Ximenia america L.,(Olacaceae) in wistar albino rats. Int J Pharm Pharm Sci, 10, 62-70.
Kurcinski, M., Oleniecki, T., Ciemny, M. P., Kuriata, A., Kolinski, A., & Kmiecik, S. (2019). CABS-flex standalone: a simulation environment for fast modeling of protein flexibility. Bioinformatics, 35(4), 694-695.
Lin, X., Li, X., & Lin, X. (2020). A review on applications of computational methods in drug screening and design. Molecules, 25(6), 1375.
López-Blanco, J. R., Aliaga, J. I., Quintana-Ortí, E. S., & Chacón, P. (2014). iMODS: internal coordinates normal mode analysis server. Nucleic Acids Research, 42(W1), W271-W276.
MacGowan, A., & Macnaughton, E. (2017). Antibiotic resistance. Medicine, 45(10), 622-628.
Maikai, V., Maikai, B. V., & Kobo, P. (2009). Antimicrobial Properties of Stem Bark Extracts of Ximenia Americana. Journal of Agricultural Science, 1, 30-34. https://doi.org/10.5539/jas.v1n2p30
Monte, F. J. Q., de Lemos, T. L. G., de Araújo, M. R. S., & de Sousa Gomes, E. (2012). Ximenia americana: chemistry, pharmacology and biological properties, a review. Phytochemicals–A Global Perspective of Their Role in Nutrition and Health, 429-450.
Ortiz, C. L. D., Completo, G. C., Nacario, R. C., & Nellas, R. B. (2019). Potential Inhibitors of Galactofuranosyltransferase 2 (GlfT2): Molecular Docking, 3D-QSAR, and In Silico ADMETox Studies. Scientific Reports, 9(1), 17096. https://doi.org/10.1038/s41598-019-52764-8
Peters, K., Schweizer, I., Hakenbeck, R., & Denapaite, D. (2021). New Insights into Beta-Lactam Resistance of Streptococcus pneumoniae: Serine Protease HtrA Degrades Altered Penicillin-Binding Protein 2x. Microorganisms, 9(8).
Pires, D. E. V., Blundell, T. L., & Ascher, D. B. (2015). pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. Journal of Medicinal Chemistry, 58(9), 4066-4072. https://doi.org/10.1021/acs.jmedchem.5b00104
Raval, K., & Ganatra, T. (2022). Basics, types and applications of molecular docking: A review. IP International Journal of Comprehensive and Advanced Pharmacology, 7(1), 12-16.
Sanner, M. F. (1999). Python: a programming language for software integration and development. Journal of Molecular Graphics and Modelling, 17(1), 57-61.
Satuluri, S. H., Katari, S. K., Pasala, C., & Amineni, U. (2020). Novel and potent inhibitors for dihydropteroate synthase of Helicobacter pylori. Journal of Receptors and Signal Transduction, 40(3), 246-256. https://doi.org/10.1080/10799893.2020.1731533
Schweizer, I., Peters, K., Stahlmann, C., Hakenbeck, R., & Denapaite, D. (2014). Penicillin-binding protein 2x of Streptococcus pneumoniae: the mutation Ala707Asp within the C-terminal PASTA2 domain leads to destabilization. Microbial Drug Resistance, 20(3), 250-257.
Sliwoski, G., Kothiwale, S., Meiler, J., & Lowe, E. W. (2014). Computational methods in drug discovery. Pharmacological Reviews, 66(1), 334-395.
Uddin, T. M., Chakraborty, A. J., Khusro, A., Zidan, B. M. R. M., Mitra, S., Emran, T. B., Dhama, K., Ripon, M. K. H., Gajdács, M., Sahibzada, M. U. K., Hossain, M. J., & Koirala, N. (2021). Antibiotic resistance in microbes: History, mechanisms, therapeutic strategies and future prospects. Journal of Infection and Public Health, 14(12), 1750-1766. https://doi.org/https://doi.org/10.1016/j.jiph.2021.10.020
Zaman, S. B., Hussain, M. A., Nye, R., Mehta, V., Mamun, K. T., & Hossain, N. (2017). A Review on Antibiotic Resistance: Alarm Bells are Ringing. Cureus, 9(6), e1403. https://doi.org/10.7759/cureus.1403
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