TYPE Original Research PUBLISHED 16 January 2025 DOI 10.3389/fvets.2024.1507496 OPEN ACCESS EDITED BY Hongbin Yan, Chinese Academy of Agricultural Sciences, China REVIEWED BY Arlex Rodríguez-Durán, Federal University of Rio Grande do Sul, Brazil Kaiqing Zhang, Biocytogen, United States *CORRESPONDENCE Chien-Chin Chen hlmarkc@gmail.com Abid Ali uop_ali@yahoo.com † These authors have contributed equally to this work RECEIVED 08 October 2024 ACCEPTED 02 December 2024 PUBLISHED 16 January 2025 CITATION Rahman S, Liu H, Shah M, Almutairi MM, Liaqat I, Tanaka T, Chen C-C, Alouffi A and Ali A (2025) Prediction of potential drug targets and key inhibitors (ZINC67974679, ZINC67982856, and ZINC05668040) against Rickettsia felis using integrated computational approaches. Front. Vet. Sci. 11:1507496. doi: 10.3389/fvets.2024.1507496 COPYRIGHT © 2025 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) and the copyright owner(s) 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. Prediction of potential drug targets and key inhibitors (ZINC67974679, ZINC67982856, and ZINC05668040) against Rickettsia felis using integrated computational approaches Sudais Rahman 1† , Hsien Liu 2† , Mohibuallah Shah 3 , Mashal M. Almutairi 4 , Iram Liaqat 5 , Tetsuya Tanaka 6 , Chien-Chin Chen 7,8,9,10 *, Abdulaziz Alouffi 11 and Abid Ali 1 * 1 Department of Zoology, Abdul Wali Khan University, Mardan, Khyber Pakhtunkhwa, Pakistan, 2 Division of General Surgery, Department of Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan, 3 Department of Biochemistry, Bahauddin Zakariya University, Multan, Pakistan, 4 Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, 5 Microbiology Lab, Department of Zoology, Government College University Lahore, Lahore, Pakistan, 6 Laboratory of Animal Microbiology, Faculty of Agriculture, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan, 7 Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan, 8 Department of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan, 9 Doctoral Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan, 10 Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan, 11 King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia 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 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 11 distinct proteins. Out of these, 10 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 non-sensitizing to the skin. Based on these findings, further Frontiers in Veterinary Science 01 frontiersin.org