Наразі відома значна кількість інгібіторів бактеріального FtsZ білка, біологічна активність яких підтверджена біохімічно, однак цільові сайти ліганд-білкової взаємодії у більшості випадків залишаються невідомими. Це значно ускладнює подальший комбінаторний дизайн, що і обумовило необхідність біоінформа-тичного пошуку ефекторів сайту міждоменної щілини цього білка (Inter-Domain Cleft = IDC). Актуальне дослідження базувалось на результатах фармакофорного скринінгу за допомогою сервісу Pharmit і результатах молекулярного докінгу з використанням програм CCDC GOLD і iGEMDOCK. Цільовою групою була об’єднана бібліотека з 379 речовин, сформована за результатами ревізії структурної бази даних RCSB Protein Data Bank і речовин бази даних ChEMBL, для яких безпосередня взаємодія з FtsZ білком доведена біохімічно. За результатами фармакофорного пошуку, докінгу і структурно-біологічного аналізу було визначено 88 ефекторів сайту IDC. Ще одна сполука ряду куркумінойдів була визначена як потенційний ефектор сайту IDC.
Ключові слова: FtsZ, білок, мждомкееа щілина, IDC, ефектори, ліганд-білкова взаємодія, фармакофорний пошук, молекулярний докінг
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Adams, D.W., Wu, L.J., Czaplewski, L.G., et al., Multiple effects of benzamide antibiotics on FtsZ function, Mol. Microbiol., 2011, vol. 80, pp. 68–84. https://doi.org/10.1111/j.1365-2958.2011.07559.x
Alnami, A., Norton, R.S., Pena, H.P., et al., Conformational flexibility of a highly conserved helix controls cryptic pocket formation in FtsZ, J. Mol. Biol., 2021, vol. 433, no. 15, p. 167061. https://doi.org/10.1016/j.jmb.2021.167061
Andreu, J.M., Schaffner-Barbero, C., and Huecas, S., The antibacterial cell division inhibitor PC190723 is an FtsZ polymer-stabilizing agent that induces filament assembly and condensation, J. Biol. Chem., 2010, vol. 285, no. 19, pp. 14239–14246. https://doi.org/10.1074/jbc.M109.094722
Andreu, J.M., Huecas, S., Araujo-Bazan, L., et al., The search for antibacterial inhibitors targeting cell division protein FtsZ at its nucleotide and allosteric binding sites, Biomedicines, 2022, vol. 10, no. 8, p. 1825. https://doi.org/10.3390/biomedicines10081825
Bellaver, E.H., da Costa, I.M., Redin, E.E., et al., The fermented milk can be a natural ally against obesity? Investigation of bovine milk fermentation by Lacticaseibacillus casei LBC 237, screening, and in silico predictions of bioactive peptides for obesity control, Intelligent Pharmacy (in press). https://doi.org/10.1016/j.ipha.2024.05.009
Bryan, E., Ferrer-Gonzalez, E., Sagong, H.Y., et al., Structural and antibacterial characterization of a new benzamide FtsZ inhibitor with superior bactericidal activity and in vivo efficacy against multidrug-resistant Staphylococcus aureus, ACS Chem. Biol., 2023, vol. 18, no. 3, pp. 629–642. https://doi.org/10.1021/acschembio.2c00934
Cramer, P., AlphaFold2 and the future of structural biology, Nat. Struct. Mol. Biol., 2021, vol. 28, no. 9, pp. 704–705. https://doi.org/10.1038/s41594-021-00650-1
Ferrer-González, E., Fujita, J., Yoshizawa, T., et al., Structure-guided design of a fluorescent probe for the visualization of FtsZ in clinically important gram-positive and gram-negative bacterial pathogens, Sci. Rep., 2019, vol. 9, no. 1, p. 20092. https://doi.org/10.1038/s41598-019-56557-x
Fujita, J., Harada, R., Maeda, Y., et al., Identification of the key interactions in structural transition pathway of FtsZ from Staphylococcus aureus, J. Struct. Biol., 2017a, vol. 198, no. 2, pp. 65–73. https://doi.org/10.1016/j.jsb.2017.04.008
Fujita, J., Maeda, Y., Mizohata, E., et al., Structural flexibility of an inhibitor overcomes drug resistance mutations in Staphylococcus aureus FtsZ, ACS Chem. Biol., 2017b, vol. 12, no. 7, pp. 1947–1955. https://doi.org/10.1021/acschembio.7b00323
Gurnani, M., Rath, P., Chauhan, A., et al., Inhibition of Filamentous thermosensitive mutant-Z protein in Bacillus subtilis by cyanobacterial bioactive compounds, Molecules, 2022, vol. 27, no. 6, p. 1907. https://doi.org/10.3390/molecules27061907
Han, H., Wang, Z., Li, T., et al., Recent progress of bacterial FtsZ inhibitors with a focus on peptides, FEBS J., 2021, vol. 288, no. 4, pp. 1091–1106. https://doi.org/10.1111/febs.15489
Haydon, D.J., Stokes, N.R., Ure, R., et al., An inhibitor of FtsZ with potent and selective anti-staphylococcal activity, Science, 2008, vol. 321, no. 5896, pp. 1673–1675. https://doi.org/10.1126/science.1159961
Hendlich, M., Rippmann, F., and Barnickel, G., LIGSITE: automatic and efficient detection of potential small molecule-binding sites in proteins, J. Mol. Graph. Model, 1997, vol. 15, no. 6, pp. 359–363. https://doi.org/10.1016/s1093-3263(98)00002-3
Hirano, Y., Okimoto, N., Fujita, S., et al., Molecular dynamics study of conformational changes of Tankyrase 2 binding subsites upon ligand binding, ACS Omega, 2021, vol. 6, no. 27, pp. 17609–17620. https://doi.org/10.1021/acsomega.1c02159
Huecas, S., Araújo-Bazán, L., Ruiz, F.M., et al., Targeting the FtsZ allosteric binding site with a novel fluorescence polarization screen, cytological and structural approaches for antibacterial discovery, J. Med. Chem., 2021, vol. 64, no. 9, pp. 5730–5745. https://doi.org/10.1021/acs.jmedchem.0c02207
Jones, G., Willett, P., Glen, R.C., et al., Development and validation of a genetic algorithm for flexible docking, J. Mol. Biol., 1997, vol. 267, no. 3, pp. 727–748. https://doi.org/10.1006/jmbi.1996.0897
Jumper, J., Evans, R., Pritzel, A., et al., Highly accurate protein structure prediction with AlphaFold, Nature, 2021, vol. 596, no. 7873, pp. 583–589. https://doi.org/10.1038/s41586-021-03819-2
Karpov, P.A., Demchuk, O.M., Britsun, V.M., et al., New imidazole inhibitors of Mycobacterial FtsZ: the way from high-throughput molecular screening in Grid up to in vitro verification, Nauka Innovats., 2016, vol. 12, no. 3, pp. 44–59. https://doi.org/10.15407/scin12.03.044
Kifayat, S., Yele, V., Ashames, A., et al., Filamentous temperature sensitive mutant Z: a putative target to combat antibacterial resistance, RSC Adv., 2023, vol. 13, no. 17, pp. 11368–11384. https://doi.org/10.1039/d3ra00013c
Löwe, J. and Amos, L.A., Crystal structure of the bacterial cell-division protein FtsZ, Nature, 1998, vol. 391, no. 6663, pp. 203–206. https://doi.org/10.1038/34472
Matsui, T., Yamane, J., Mogi, N., et al., Structural reorganization of the bacterial cell-division protein FtsZ from Staphylococcus aureus, Acta Crystallogr., Sect. D: Biol. Crystallogr., 2012, vol. 68, pp. 1175–1188. https://doi.org/10.1107/S0907444912022640
Ozheriedov, D.S., Ozheredov, S.P., Demchuk, O.M., Blume, Ya.B., and Karpov, P.A., Ligand-induced variability of the FtsZ protein InterDomain Cleft site pocket, Cyt. Genet., 2024, vol. 58, no. 4. https://doi.org/IN PRINT
Pradhan, P., Margolin, W., and Beuria, T.K., Targeting the achilles heel of FtsZ: the interdomain cleft, Front. Microbiol., 2021, vol. 12, p. 732796. https://doi.org/10.3389/fmicb.2021.732796
Ramírez-Aportela, E., López-Blanco, J.R., Andreu, J.M., et al., Understanding nucleotide-regulated FtsZ filament dynamics and the monomer assembly switch with large-scale atomistic simulations, Biophys. J., 2014, vol. 107, no. 9, pp. 2164–2176. https://doi.org/10.1016/j.bpj.2014.09.033
Sharma, A.K., Poddar, S.M., Chakraborty, J., et al., A mechanism of salt bridge-mediated resistance to FtsZ inhibitor PC190723 revealed by a cell-based screen, Mol. Biol. Cell., 2023, vol. 34, no. 3, p. ar16. https://doi.org/10.1091/mbc.E22-12-0538
Steinkellner, G., Rader, R., and Thallinger, G.G., VASCo: computation and visualization of annotated protein surface contacts, BMC Bioinf., 2009, vol. 10, p. 32. https://doi.org/10.1186/1471-2105-10-32
Stokes, N.R., Baker, N., Bennett, J.M., et al., An improved small-molecule inhibitor of FtsZ with superior in vitro potency, drug-like properties, and in vivo efficacy, Antimicrob. Agents Chemother., 2013, vol. 57, no. 1, pp. 317–325. https://doi.org/10.1128/AAC.01580-12
Sunseri, J., Koes, D.R., Pharmit: interactive exploration of chemical space, Nucleic Acids Res., 2016, vol. 44, no. W1, pp. W442–W448. https://doi.org/10.1093/nar/gkw287
Tan, C.M., Therien, A.G., Lu, J., Lee, S.H., et al., Restoring methicillin-resistant Staphylococcus aureus susceptibility to β-lactam antibiotics, Sci. Transl. Med., 2012, vol. 4, no. 126, p. 126ra35. https://doi.org/10.1126/scitranslmed.3003592
UniProt Consortium, UniProt: the Universal Protein Knowledgebase in 2023, Nucleic Acids Res., 2023, vol. 51, no. D1, pp. D523–D531. https://doi.org/10.1093/nar/gkac1052
Wagstaff, J.M., Tsim, M., Oliva, M.A., et al., Polymerization-associated structural switch in FtsZ that enables treadmilling of model filaments, mBio, 2017, vol. 8, no. 3, p. e00254-17. https://doi.org/10.1128/mBio.00254-17
Wang, M., Fang, C., Ma, B., et al., Regulation of cytokinesis: FtsZ and its accessory proteins, Curr. Genet., 2020, vol. 66, no. 1, pp. 43–49. https://doi.org/10.1007/s00294-019-01005-6
Wang, M., Wu, Z., Wang, J., et al., Genetic algorithm-based receptor ligand: A genetic algorithm-guided generative model to boost the novelty and drug-likeness of molecules in a sampling chemical space, J. Chem. Inf. Model., 2024, vol. 64, no. 4, pp. 1213–1228. https://doi.org/10.1021/acs.jcim.3c01964
Waterhouse, A., Bertoni, M., Bienert, S., et al., SWISS-MODEL: homology modelling of protein structures and complexes, Nucleic Acids Res., 2018, vol. 46, no. W1, pp. W296–W303. https://doi.org/10.1093/nar/gky427
Yang, J.M., Development and evaluation of a generic evolutionary method for protein-ligand docking, J. Comput. Chem., 2004, vol. 25, no. 6, pp. 843–857. https://doi.org/10.1002/jcc.20013
Yang, J.M. and Chen, C.C., GEMDOCK: a generic evolutionary method for molecular docking, Proteins, 2004, vol. 55, no. 2, pp. 288–304. https://doi.org/10.1002/prot.20035