Antibacterial Potential of Ximenia americana L. Olacaceae: Molecular Docking, Molecular Dynamics, and ADMET Prediction
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Abstract
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.
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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. DOI: https://doi.org/10.22236/j.bes/515091
Askari, S. B., & Krajinovic, M. (2010). Dihydrofolate reductase gene variations in susceptibility to disease and treatment outcomes. Current genomics, 11(8), 578-583. DOI: https://doi.org/10.2174/138920210793360925
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. DOI: https://doi.org/10.1155/2022/3486257
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 DOI: 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 DOI: https://doi.org/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 DOI: 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. DOI: https://doi.org/10.14421/biomedich.2023.121.281-288
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. DOI: https://doi.org/10.58920/sciphar02030024
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. DOI: https://doi.org/10.30574/gscbps.2022.21.3.0462
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. DOI: https://doi.org/10.1038/srep42717
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 DOI: 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 DOI: https://doi.org/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. DOI: https://doi.org/10.5530/pj.2019.11.55
Gajdács, M., & Albericio, F. (2019). Antibiotic resistance: from the bench to patients. Antibiotics, 8(3), 129. DOI: https://doi.org/10.3390/antibiotics8030129
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 DOI: https://doi.org/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 DOI: 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. DOI: https://doi.org/10.1016/j.neuron.2018.08.011
Hooper, D. C., & Jacoby, G. A. (2016). Topoisomerase inhibitors: fluoroquinolone mechanisms of action and resistance. Cold Spring Harbor Perspectives in Medicine, 6(9), a025320. DOI: https://doi.org/10.1101/cshperspect.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 DOI: https://doi.org/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 DOI: 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 DOI: 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. DOI: https://doi.org/10.4103/joacp.JOACP_349_15
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. DOI: https://doi.org/10.22159/ijpps.2018v10i10.25485
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. DOI: https://doi.org/10.1093/bioinformatics/bty685
Lin, X., Li, X., & Lin, X. (2020). A review on applications of computational methods in drug screening and design. Molecules, 25(6), 1375. DOI: https://doi.org/10.3390/molecules25061375
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. DOI: https://doi.org/10.1093/nar/gku339
MacGowan, A., & Macnaughton, E. (2017). Antibiotic resistance. Medicine, 45(10), 622-628. DOI: https://doi.org/10.1016/j.mpmed.2017.07.006
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 DOI: 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 DOI: 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). DOI: https://doi.org/10.3390/microorganisms9081685
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 DOI: 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. DOI: https://doi.org/10.18231/j.ijcaap.2022.003
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 DOI: 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. DOI: https://doi.org/10.1089/mdr.2014.0082
Sliwoski, G., Kothiwale, S., Meiler, J., & Lowe, E. W. (2014). Computational methods in drug discovery. Pharmacological Reviews, 66(1), 334-395. DOI: https://doi.org/10.1124/pr.112.007336
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 DOI: 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 DOI: https://doi.org/10.7759/cureus.1403