Abstract:

Researchers are trying to develop new antibiotics by targeting cellular components due to the emergence of antibiotic resistance by microbes. In this study, three targets were chosen these are penicillin binding protein-4, cell division protein, FtsA and shikimate dehydrogenase enzyme. Their binding sites were predicted online by RaptorX and GalaxyWEB servers. Virtual screening was carried out using the AutoDock Vina tool for a total of 50 experimental and approved compounds selected from the Drug Bank database. The results were redocked again by iGEMDOCK and the online SWISS-DOCK server. The top ten compounds in AutoDock Vina were selected. In Pharcokinetics and pharmacodynamics study in silico, the highest three compounds in docking scores, Flunisolide, Doxazosin and Isradipine, showed high absorption by the gastrointestinal route and did not appear to cross blood blood-brain carrier, but the last two showed a probability of drug interaction via cytochrome. Hence, the study of pharmacokinetics and toxicities is crucial in the drug design approach. The use of more than one tool is preferred to obtain more reliable results.

References:

[1].   Gonzalez-Bello, C., 2016, Inhibition of shikimate kinase and type II dehydroquinase for antibiotic discovery: structure-based design and simulation studies. Current Topics in Medicinal Chemistry, 16(9), 960-977.

[2].   Belete, T. M., 2019, Novel targets to develop new antibacterial agents and novel alternatives to antibacterial agents. Human Microbiome Journal, 11, 100052. Doi:10.1016/j.humic.2019.01.001.

[3].   Hussein, M. J. A., Delool, R. A., Al-Fahham, H. R., 2024, Study of the Bacteria Associated with Acute Urinary Tract Infection in Human. Journal of Natural Science, Biology and Medicine, 15(2), 190. Doi:10.4103/jnsbm.JNSBM_15_2_3.

[4].   Sauvage, E., Kerff, F., Terrak, M., Ayala, J. A., Charlier, P., 2008, The penicillin-binding proteins: structure and role in peptidoglycan biosynthesis. FEMS microbiology reviews, 32(2), 234-258. Doi:10.1111/j.1574-6976.2008.00105.x.

[5].   Vollmer, W., Blanot, D., De Pedro, M. A., 2008, Peptidoglycan structure and architecture. FEMS microbiology reviews, 32(2), 149-167. Doi:10.1111/j.1574-6976.2007.00094.x.

[6].   Feucht, A., Lucet, I., Yudkin, M. D., Errington, J., 2001, Cytological and biochemical characterization of the FtsA cell division protein of Bacillus subtilis. Molecular microbiology, 40(1), 115-125. Doi:10.1046/j.1365-2958.2001.02356.x.

[7].   Margolin, W., 2005, FtsZ and the division of prokaryotic cells and organelles. Nature reviews Molecular cell biology, 6(11), 862-871. Doi:10.1038/nrm1745.

[8].   Krupka, M., Rowlett, V. W., Morado, D., Vitrac, H., Schoenemann, K., Liu, J., Margolin, W., 2017, Escherichia coli FtsA forms lipid-bound minirings that antagonize lateral interactions between FtsZ protofilaments. Nature communications, 8(1), 15957. Doi:10.1038/ncomms15957.

[9].   Källberg, M., Wang, H., Wang, S., Peng, J., Wang, Z., Lu, H., Xu, J., 2012, Template-based protein structure modeling using the RaptorX web server. Nature protocols, 7(8), 1511-1522.  Doi:10.1038/nprot.2012.085.

[10].  Shin, W. H., Lee, G. R., Heo, L., Lee, H., Seok, C. J. B. D., 2014, Prediction of protein structure and interaction by GALAXY protein modeling programs. Bio Design, 2(1), 1-11.

[11].  Wishart, D. S., Knox, C., Guo, A. C., Cheng, D., Shrivastava, S., Tzur, D., Hassanali, M., 2008, DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic acids research, 36(suppl_1), D901-D906. Doi:10.1093/nar/gkm958.

[12].  Trott, O., Olson, A. J., 2010, 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. Doi:10.1002/jcc.21334.

[13].  Wallace, A. C., Laskowski, R. A., Thornton, J. M., 1995, LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein engineering, design and selection, 8(2), 127-134. https://doi.org/10.1093/protein/8.2.127.

[14].  Hsu, K. C., Chen, Y. F., Lin, S. R., Yang, J. M., 2011, iGEMDOCK: a graphical environment of enhancing GEMDOCK using pharmacological interactions and post-screening analysis. BMC bioinformatics, 12, 1-11. Doi:10.1186/1471-2105-12-S1-S33.

[15].  Grosdidier, A., Zoete, V., Michielin, O., 2011, SwissDock, a protein-small molecule docking web service based on EADock DSS. Nucleic acids research, 39(suppl_2), W270-W277. Doi:10.1093/nar/gkr366.

[16].  Daina, A., Michielin, O., Zoete, V., 2017, Swiss ADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific reports, 7(1), 42717. Doi:10.1038/srep42717.

[17].  Goffin, C., Ghuysen, J. M., 1998, Multimodular penicillin-binding proteins: an enigmatic family of orthologs and paralogs. Microbiology and molecular biology reviews, 62(4), 1079-1093. Doi:10.1128/mmbr.62.4.1079-1093.1998.

[18].  Born, P., Breukink, E., Vollmer, W., 2006, In vitro synthesis of cross-linked murein and its attachment to sacculi by PBP1A from Escherichia coli. Journal of Biological Chemistry, 281(37), 26985-26993. Doi:10.1074/jbc.M604083200.

[19].  Sauvage, E., Herman, R., Petrella, S., Duez, C., Bouillenne, F., Frere, J. M., Charlier, P., 2005, Crystal structure of the Actinomadura R39 DD-peptidase reveals new domains in penicillin-binding proteins. Journal of Biological Chemistry, 280(35), 31249-31256. Doi:10.1074/jbc.M503271200.

[20].  Kishida, H., Unzai, S., Roper, D. I., Lloyd, A., Park, S. Y., Tame, J. R., 2006, Crystal structure of penicillin binding protein 4 (dacB) from Escherichia coli, both in the native form and covalently linked to various antibiotics. Biochemistry, 45(3), 783-792. Doi:10.1021/bi051533t.

[21].  Fujita, J., Maeda, Y., Nagao, C., Tsuchiya, Y., Miyazaki, Y., Hirose, M., Matsumura, H., 2014, Crystal structure of FtsA from Staphylococcus aureus. FEBS letters, 588(10), 1879-1885. Doi:10.1016/j.febslet.2014.04.008.

[22].  van den Ent, F., Löwe, J., 2000, Crystal structure of the cell division protein FtsA from Thermotoga maritima. The EMBO journal. 19(20): 5300-5307. Doi:10.1093/emboj/19.20.5300.

[23].  Michel, G., Roszak, A. W., Sauvé, V., Maclean, J., Matte, A., Coggins, J. R., Lapthorn, A. J., 2003, Structures of shikimate dehydrogenase AroE and its paralog YdiB: a common structural framework for different activities. Journal of Biological Chemistry, 278(21), 19463-19472. Doi:10.1074/jbc.M300794200.

[24].  Ye, S., Von Delft, F., Brooun, A., Knuth, M. W., Swanson, R. V., McRee, D. E., 2003, The crystal structure of shikimate dehydrogenase (AroE) reveals a unique NADPH binding mode. Journal of bacteriology, 185(14), 4144-4151. Doi:10.1128/jb.185.14.4144-4151.2003.

[25].  Waugh, J., Goa, K. L., 2002, Flunisolide HFA. American Journal of Respiratory Medicine, 1, 369-372. Doi:10.1007/BF03256630.

[26].  Yuan, J., Liu, Y., Yang, Z., Qin, X., Yang, K., Mao, C., 2013, The efficacy and safety of alpha-1 blockers for benign prostatic hyperplasia: an overview of 15 systematic reviews. Current medical research and opinion, 29(3), 279-287. Doi:10.1185/03007995.2013.766594.

[27].  Ganz, M., Mokabberi, R., Sica, D. A., 2005, Comparison of blood pressure control with amlodipine and controlled‐release isradipine: an open‐label, drug substitution study. The Journal of Clinical Hypertension, 7, 27-31. Doi:10.1111/j.1524-6175.2005.04450.x.

[28].  Alves, M. J., Froufe, H. J., Costa, A. F., Santos, A. F., Oliveira, L. G., Osório, S. R., Ferreira, I.C., 2014, Docking studies in target proteins involved in antibacterial action mechanisms: Extending the knowledge on standard antibiotics to antimicrobial mushroom compounds. Molecules, 19(2), 1672-1684. Doi:10.3390/molecules19021672.

[29].  Kulanthaivel, L., Jeyaraman, J., Biswas, A., Subbaraj, G. K., Santhoshkumar, S., 2018, Identification of potential inhibitors for Penicillinbinding protein (PBP) from Staphylococcus aureus. Bioinformation, 14(9), 471. Doi:10.6026/97320630014471.

[30].  Isa, M. A., Majumdar, R. S., Haider, S., 2019, In silico identification of potential inhibitors against shikimate dehydrogenase through virtual screening and toxicity studies for the treatment of tuberculosis. International Microbiology, 22, 7-17. Doi:10.1007/s10123-018-0021-2.

[31].  de la Nuez, A., Rodríguez, R., 2008, Current methodology for the assessment of ADME-Tox properties on drug candidate molecules. Biotecnología Aplicada, 25(2), 97-110.

[32].  Williams, J. A., Hyland, R., Jones, B. C., Smith, D. A., Hurst, S., Goosen, T. C., Ball, S. E., 2004, Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metabolism and Disposition, 32(11), 1201-1208. Doi:10.1124/dmd.104.000794.

[33].  Ogu, C. C., Maxa, J. L., 2000, Drug interactions due to cytochrome P450. In Baylor University medical center proceedings, 13(4): 421-423. Doi:10.1080/08998280.2000.11927719.

[34].  Behera, A., Yamuna devi, M. S., Ryntathiang, I., Mukesh Kumar Dharmalingam Jothinathan, 2024, Green Synthesis of Selenium Nanoparticles using Cinnamomum Verum Extract and their Antibacterial, Antioxidant, and Brine Shrimp Toxicity Effects. Texila International Journal of Public Health, 12(3): 1-13, Doi:10.21522/TIJPH.2013.12.03.Art039.

[35].  Mandapati, K. K., Uma, C., Sivagurunathan, P., Senapati, S., Manogaran, Y., Ramasamy, P., 2024, Prevalence of Multi-Drug Resistant Bacterial Isolates in Healthcare Environments. Texila International Journal of Public Health, 12(4): 1-10, Doi:10.21522/TIJPH.2013.12.04.Art007.

[36].  Yunus, R., Wijayati, F., Askrening, A., Rahayu, D. Y. S., Hasan, F. E., Trees, T., Fusvita, A., 2024. Diabetes Mellitus and Bacterial Infections: A Review of Main Infections in DM Patients. Public Health of Indonesia, 10(1), 73-97. Doi:10.36685/Phi.V10i1.777.