MOLECULAR DOCKING–BASED ANALYSIS AND ANTIBACTERIAL ACTIVITY EVALUATION OF RIFAXIMIN
DOI:
https://doi.org/10.5281/zenodo.19106592Anahtar Kelimeler:
Rifaksimin, E. coli, RfaH protein, moleküler kenetlenmeÖzet
Rifamisin grubundan türetilen yarı sentetik bir antibiyotik olan rifaksimin, özellikle gastrointestinal enfeksiyonların yönetiminde yaygın olarak kullanılmaktadır. Düşük sistemik biyoyararlanımı nedeniyle, ilaç ağırlıklı olarak bağırsaklarda lokalize kalır ve sistemik yan etkileri en aza indirirken antibakteriyel etkilerini göstermesine izin verir. Rifaksimin, bakterilerdeki RNA polimeraz enzimine geri dönüşümsüz olarak bağlanarak işlevini engelleyerek çalışır. Bu çalışmada, rifaksiminin E. coli'nin RfaH proteini ile ligand-reseptör kompleksi moleküler kenetlenme yöntemleri kullanılarak incelenmiştir. Moleküler kenetlenme simülasyonları YASARA programında VINA yaklaşımı kullanılarak gerçekleştirilmiş ve rifaksimin-RfaH kompleksine ilişkin bulgular elde edilmiştir. Bulgular, rifaksimin'in E. coli'yi inhibe etmedeki terapötik potansiyeli ve klinik ortamlardaki olası uygulamaları hakkında değerli bilgiler sağlamaktadır. Bileşiğin antibakteriyel, antifungal ve antiviral aktiviteleri AntiBac-Pred, AntiFun-Pred ve AntiVir-Pred kullanılarak tahmin edilmiştir. Moleküler kenetlenme modelleri, Rifaximin'in RfaH proteinine -7.792 kcal/mol bağlanma afinitesine ve hedefle etkileşimlerine dayanarak önemli bir antibakteriyel etkiye sahip olacağını göstermektedir. Bu veriler Rifaximin'in Prevotella disiens (confidence: 0.9715), Bacteroides stercoris (confidence: 0.9685), Clostridium ramosum (confidence: 0.9557) ve Porphyromonas asaccharolytica'ya (confidence: 0.9235) karşı etkili olabileceğini göstermektedir.
Referanslar
Ashraf, A., Choudhary, A., Khan, M. A., & others. (2024). Repurposing rifaximin against
Klebsiella pneumoniae via targeting of transcription anti-termination protein RfaH for novel antimicrobial development [Preprint]. Research Square. https://doi.org/10.21203/rs.3.rs-4724428/v1
Belogurov, G. A., Vassylyeva, M. N., Svetlov, V., Klyuyev, S., Grishin, N. V., Vassylyev, D. G.,
& Artsimovitch, I. (2007). Structural basis for converting a general transcription factor into an operon-specific virulence regulator. Molecular cell, 26(1), 117-129.
Brown ED, Wright GD (2016). Antibacterial drug discovery in the resistance era. Nature.
;529(7586):336-343.
Calanni, F., Renzulli, C., Barbanti, M., & Viscomi, G. C. (2014). Rifaximin: Beyond the
traditional antibiotic activity. The Journal of Antibiotics, 67(9), 667–670. https://doi.org/10.1038/ja.2014.106
Campbell, E. A., Korzheva, N., Mustaev, A., Murakami, K., Nair, S., Goldfarb, A., & Darst, S.
A. (2001). Structural mechanism for rifampicin inhibition of bacterial rna polymerase. Cell, 104(6), 901–912. https://doi.org/10.1016/s0092-8674(01)00286-0
Filimonov DA, Lagunin AA, Gloriozova TA, et al. (2014). Prediction of the biological activity
spectra of organic compounds using the PASS online web resource. Chem Heterocycl Compd. (2014);50(3):444-457.
Fourches D, Muratov E, Tropsha A (2015). Curation of chemogenomics data. Nat. Chem. Biol.
(2015);11(8):535-535.
Gaulton A, Hersey A, Nowotka M, et al. (2017). The ChEMBL database in 2017. Nucleic Acids
Res. (2017);45(D1):D945-D954.
GC, J. B., Bhandari, Y. R., Gerstman, B. S., & Chapagain, P. P. (2014). Molecular dynamics
investigations of the α-helix to β-barrel conformational transformation in the RfaH transcription factor. The Journal of Physical Chemistry B, 118(19), 5101–5108. https://doi.org/10.1021/jp502193v
Gillis, J. C., & Brogden, R. N. (1995). Rifaximin. A review of its antibacterial activity,
pharmacokinetic properties and therapeutic potential in conditions mediated by gastrointestinal bacteria. Drugs, 49(3), 467–484. https://doi.org/10.2165/00003495-199549030-00009
Hirota, S. A. (2016). Understanding the molecular mechanisms of rifaximin in the treatment of
gastrointestinal disorders – A focus on the modulation of host tissue function. Mini-Reviews in Medicinal Chemistry, 16(3), 206–217. https://doi.org/10.2174/1389557515666150722105705
Hoover, W. W., Gerlach, E. H., Hoban, D. J., Eliopoulos, G. M., Pfaller, M. A., & Jones, R. N.
(1993). Antimicrobial activity and spectrum of rifaximin, a new topical rifamycin derivative. Diagnostic microbiology and infectious disease, 16(2), 111–118. https://doi.org/10.1016/0732-8893(93)90004-q
Hustmyer, C. M., Wolfe, M. B., Welch, R. A., & Landick, R. (2022). RfaH Counter-Silences
Inhibition of Transcript Elongation by H-NS-StpA Nucleoprotein Filaments in Pathogenic Escherichia coli. mBio, 13(6), e0266222. https://doi.org/10.1128/mbio.02662-22
Jiang, Z. D., & DuPont, H. L. (2005). Rifaximin: in vitro and in vivo antibacterial activity--a
review. Chemotherapy, 51 Suppl 1, 67–72. https://doi.org/10.1159/000081991
Krieger, E., Koraimann, G., & Vriend, G. (2002). Increasing the precision of comparative
models with YASARA NOVA—a self‐parameterizing force field. Proteins: Structure, Function, and Bioinformatics, 47(3), 393-402.
Krieger, E., & Vriend, G. (2014). YASARA View—molecular graphics for all devices—from
smartphones to workstations. Bioinformatics, 30(20), 2981-2982.
Lengauer, T., & Rarey, M. (1996). Computational methods for biomolecular docking. Current
opinion in structural biology, 6(3), 402–406. https://doi.org/10.1016/s0959-440x(96)80061-3
McClure, W. R., & Cech, C. L. (1978). On the mechanism of rifampicin inhibition of RNA
synthesis. The Journal of biological chemistry, 253(24), 8949–8956.
Naqvi, A. A. T., Mohammad, T., Hasan, G. M., & Hassan, M. I. (2018). Advancements in
docking and molecular dynamics simulations towards ligand-receptor interactions and structure-function relationships. Current Topics in Medicinal Chemistry, 18(20), 1755–1768. https://doi.org/10.2174/1568026618666181025114157
Ojetti, V., Lauritano, E. C., Barbaro, F., Migneco, A., Ainora, M. E., Fontana, L., … Gasbarrini,
A. (2009). Rifaximin pharmacology and clinical implications. Expert Opinion on Drug Metabolism & Toxicology, 5(6), 675–682. https://doi.org/10.1517/17425250902973695
Pimentel, M. (2009). Review of rifaximin as treatment for SIBO and IBS. Expert Opinion on
Investigational Drugs, 18(3), 349–358. https://doi.org/10.1517/13543780902780175
Pogodin PV, Lagunin AA, Filimonov DA, Poroikov VV (2015). PASS Targets: Ligand-based
multi-target computational system based on a public data and naïve Bayes approach. SAR QSAR Environ. Res. (2015);26(10):783-793.
Pogodin PV, Lagunin AA, Rudik AV, et al. (2018). How to Achieve Better Results Using PASS-
Based Virtual Screening: Case Study for Kinase Inhibitors. Front. Chem. (2018);6(133):1-14.
Pogodin PV, Lagunin AA, Rudik AV, et al. (2019). AntiBac-Pred: A web application for
predicting antibacterial activity of chemical compounds. J. Chem. Inf. Model. (2019);59(11):4513-4518.
Scarpignato, C., & Pelosini, I. (2005). Rifaximin, a poorly absorbed antibiotic: pharmacology
and clinical potential. Chemotherapy, 51 Suppl 1, 36–66. https://doi.org/10.1159/000081990
Seifi, B., Aina, A., & Wallin, S. (2021). Structural fluctuations and mechanical stabilities of the
metamorphic protein RfaH. Proteins, 89(3), 289–300. https://doi.org/10.1002/prot.26014)
Surette, M. D., Spanogiannopoulos, P., & Wright, G. D. (2021). The enzymes of the rifamycin
antibiotic resistome. Accounts of Chemical Research, 54(9), 2065–2075. https://doi.org/10.1021/acs.accounts.1c00048
Svetlov, D., Shi, D., Twentyman, J., Nedialkov, Y., Rosen, D. A., Abagyan, R., & Artsimovitch,
I. (2018). In silico discovery of small molecules that inhibit RfaH recruitment to RNA polymerase. Molecular microbiology, 110(1), 128–142. https://doi.org/10.1111/mmi.14093
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.
Van Vlem, B., Vanholder, R., De Paepe, P., Vogelaers, D., & Ringoir, S. (1996).
Immunomodulating effects of antibiotics: literature review. Infection, 24(4), 275–291. https://doi.org/10.1007/BF01743360
İndir
Yayınlanmış
Nasıl Atıf Yapılır
Sayı
Bölüm
Lisans
Telif Hakkı (c) 2026 International Journal of Sustainability

Bu çalışma Creative Commons Attribution 4.0 International License ile lisanslanmıştır.