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Screening inhibitors against the Ef-Tu of Fusobacterium nucleatum: a docking, ADMET and PBPK assessment study

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Abstract

The oral pathogen Fusobacterium nucleatum has recently been associated with an elevated risk of colorectal cancer (CRC), endometrial metastasis, chemoresistance, inflammation, metastasis, and DNA damage, along with several other diseases. This study aimed to explore the disruption of protein machinery of F. nucleatum via inhibition of elongation factor thermo unstable (Ef-Tu) protein, through natural products. No study on Ef-Tu inhibition by natural products or in Fusobacterium spp. exists till todate. Ef-Tu is an abundant specialized drug target in bacteria that varies from human Ef-Tu. Elfamycins target Ef-Tu and hence, Enacyloxin IIa was used to generate pharmacophore for virtual screening of three natural product libraries, Natural Product Activity and Species Source (NPASS) (n = 30000 molecules), Tibetan medicinal plant database (n = 54 molecules) and African medicinal plant database (n > 6000 molecules). Peptaibol Septocylindrin B (NPC141050), Hirtusneanoside, and ZINC95486259 were prioritized from these libraries as potential therapeutic candidates. ADMET profiling was done for safety assessment, physiological-based pharmacokinetic modeling in human and mouse for getting insight into drug interaction with body tissues and molecular dynamics was used to assess stability of the best hit NPC141050 (Septocylindrin B). Based on the promising results, we propose further in vitro, in vivo and pharmacokinetic testing on the lead Septocylindrin B, for possible translation into therapeutic interventions.

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All data used or generated in this study are provided as accession number or relevant information as tables or supplementary data with the manuscript.

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Acknowledgements

The authors extend their appreciation to the Deanship of Scientific Research at Shaqra University for funding this research through project number SU-ANN-202211.

Funding

This research was funded by the Deanship of Scientific Research at Shaqra University Research Support Program under the code SU-ANN-202211.

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Authors and Affiliations

  1. Clinical Laboratory Science Department, College of Applied Medical Sciences, Shaqra University, 11961, Al-Quwayiyah, Saudi Arabia

    Ahmad Alzamami

  2. Clinical Laboratory Science Department, College of Applied Medical Sciences, King Saud University, 11433, Riyadh, Saudi Arabia

    Norah A. Alturki

  3. Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan

    Kanwal Khan

  4. Alpha Genomics (Private) Limited, Islamabad, 45710, Pakistan

    Zarrin Basharat

  5. Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, 61441, Najran, Saudi Arabia

    Mutaib M. Mashraqi

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  1. Ahmad Alzamami
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  2. Norah A. Alturki
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  3. Kanwal Khan
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  4. Zarrin Basharat
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  5. Mutaib M. Mashraqi
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Contributions

AA, ZB, and NAA conceived and designed the study; ZB performed the experiments; AA, MMM validated the findings. ZB and KK wrote the original draft; MMM, NAA and AA wrote, reviewed, and edited the manuscript; AA, MMM and ZB provided software, resource support, and validated findings; MMM and ZB supervised the study; ZB and AA operated funding acquisition. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Zarrin Basharat or Mutaib M. Mashraqi.

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Alzamami, A., Alturki, N.A., Khan, K. et al. Screening inhibitors against the Ef-Tu of Fusobacterium nucleatum: a docking, ADMET and PBPK assessment study. Mol Divers (2024). https://doi.org/10.1007/s11030-024-10815-x

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