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ORIGINAL RESEARCH article

Front. Vet. Sci.
Sec. Parasitology
Volume 11 - 2024 | doi: 10.3389/fvets.2024.1507496
This article is part of the Research Topic Parasites in One Health Interface View all 12 articles

Prediction of Potential Drug Targets and Key Inhibitors (ZINC67974679, ZINC67982856, and ZINC05668040) Against Rickettsia felis Using Integrated Computational ApproachesPrediction of Potential Drug Targets in Rickettsia felis and Their Inhibitors; Using Subtractive Proteomics, Molecular Docking, Virtual Screening, and ADMET Profiling

Provisionally accepted
Sudais Rahman Sudais Rahman 1Hsien Liu Hsien Liu 2Mohibullah Shah Mohibullah Shah 3Mashal Almutairi Mashal Almutairi 4Iram Liaqat Iram Liaqat 5Tetsuya Tanaka Tetsuya Tanaka 6Chien-Chin Chen Chien-Chin Chen 2*Abdulaziz Alouffi Abdulaziz Alouffi 7Abid Ali Abid Ali 1*
  • 1 Abdul Wali Khan University Mardan, Mardan, Pakistan
  • 2 Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
  • 3 Bahauddin Zakariya University, Multan, Punjab, Pakistan
  • 4 King Saud University, Riyadh, Riyadh, Saudi Arabia
  • 5 Government College University, Lahore, Lahore, Punjab, Pakistan
  • 6 Tohoku University, Sendai, Miyagi, Japan
  • 7 King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia

The final, formatted version of the article will be published soon.

    Rickettsia felis, responsible for flea-borne spotted fever, is a rising zoonotic pathogen posing an increasing global threat due to its expanding geographical distribution. The rise in antibiotic-resistant strains of this pathogen underscores the urgent need for new therapeutic interventions. This study employed a comprehensive subtractive proteomics analysis of the R. felis proteome, aiming to identify essential, non-host homologous, and pathogen-specific proteins, which were subsequently evaluated as potential novel new drug targets. These findings offer valuable insights into the development of therapeutic strategies against rickettsiosis. The analysis revealed 343 proteins that are non-homologous to the host, including 108 essential proteins, 25 unique metabolic pathways, and eleven distinct proteins. Out of these, ten proteins were druggable in which two associated with virulence, and one related to resistance (succinate dehydrogenase). Through a rigorous screening process and extensive literature review, succinate dehydrogenase emerged as a promising drug target. Protein interaction partners for succinate dehydrogenase were identified using the STRING database. To further assess the functionality of succinate dehydrogenase, structure-based studies were conducted. Approximately 18,000 ZINC compounds were screened, leading to the finding of six potential inhibitors: ZINC67847806, ZINC67982856, ZINC67974679, ZINC67895371, ZINC05668040, and ZINC05670149. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling confirmed that most compounds met the preferred pharmacokinetic properties, except for ZINC67895371 and ZINC67847806, which exhibited positive ames test results, and ZINC05670149, ZINC67895371, and ZINC67847806, showed hepatotoxicity. All compounds were found to be nonsensitizing to the skin. Based on these findings, further experimental validation of ZINC67974679, ZINC67982856, and ZINC05668040 is recommended.

    Keywords: Rickettsia felis, novel drug targets, Succinate Dehydrogenase, In silico screening, pharmacokinetics.subtractive proteomics, molecular docking, Virtual Screening, ADMET analysis

    Received: 08 Oct 2024; Accepted: 02 Dec 2024.

    Copyright: © 2024 Rahman, Liu, Shah, Almutairi, Liaqat, Tanaka, Chen, Alouffi and Ali. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Chien-Chin Chen, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, 539, Taiwan
    Abid Ali, Abdul Wali Khan University Mardan, Mardan, Pakistan

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.