Prediction of potential drug targets and key inhibitors (ZINC67974679, ZINC67982856, and ZINC05668040) against Rickettsia felis using integrated computational approaches
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 s...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-01-01
|
| Series: | Frontiers in Veterinary Science |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fvets.2024.1507496/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841526678852993024 |
|---|---|
| author | Sudais Rahman Hsien Liu Mohibuallah Shah Mashal M. Almutairi Iram Liaqat Tetsuya Tanaka Chien-Chin Chen Chien-Chin Chen Chien-Chin Chen Chien-Chin Chen Abdulaziz Alouffi Abid Ali |
| author_facet | Sudais Rahman Hsien Liu Mohibuallah Shah Mashal M. Almutairi Iram Liaqat Tetsuya Tanaka Chien-Chin Chen Chien-Chin Chen Chien-Chin Chen Chien-Chin Chen Abdulaziz Alouffi Abid Ali |
| author_sort | Sudais Rahman |
| collection | DOAJ |
| description | 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 experimental validation of ZINC67974679, ZINC67982856, and ZINC05668040 is recommended. |
| format | Article |
| id | doaj-art-c4907adc7b5a43d9a49480def27c54cb |
| institution | Kabale University |
| issn | 2297-1769 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Veterinary Science |
| spelling | doaj-art-c4907adc7b5a43d9a49480def27c54cb2025-01-16T14:01:25ZengFrontiers Media S.A.Frontiers in Veterinary Science2297-17692025-01-011110.3389/fvets.2024.15074961507496Prediction of potential drug targets and key inhibitors (ZINC67974679, ZINC67982856, and ZINC05668040) against Rickettsia felis using integrated computational approachesSudais Rahman0Hsien Liu1Mohibuallah Shah2Mashal M. Almutairi3Iram Liaqat4Tetsuya Tanaka5Chien-Chin Chen6Chien-Chin Chen7Chien-Chin Chen8Chien-Chin Chen9Abdulaziz Alouffi10Abid Ali11Department of Zoology, Abdul Wali Khan University, Mardan, Khyber Pakhtunkhwa, PakistanDivision of General Surgery, Department of Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, TaiwanDepartment of Biochemistry, Bahauddin Zakariya University, Multan, PakistanDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi ArabiaMicrobiology Lab, Department of Zoology, Government College University Lahore, Lahore, PakistanLaboratory of Animal Microbiology, Faculty of Agriculture, Graduate School of Agricultural Science, Tohoku University, Sendai, JapanDepartment of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, TaiwanDepartment of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan, TaiwanDoctoral Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan0Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan1King Abdulaziz City for Science and Technology, Riyadh, Saudi ArabiaDepartment of Zoology, Abdul Wali Khan University, Mardan, Khyber Pakhtunkhwa, PakistanRickettsia 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 experimental validation of ZINC67974679, ZINC67982856, and ZINC05668040 is recommended.https://www.frontiersin.org/articles/10.3389/fvets.2024.1507496/fullRickettsia felisnovel drug targetssuccinate dehydrogenasein silico screeningpharmacokinetics |
| spellingShingle | Sudais Rahman Hsien Liu Mohibuallah Shah Mashal M. Almutairi Iram Liaqat Tetsuya Tanaka Chien-Chin Chen Chien-Chin Chen Chien-Chin Chen Chien-Chin Chen Abdulaziz Alouffi Abid Ali Prediction of potential drug targets and key inhibitors (ZINC67974679, ZINC67982856, and ZINC05668040) against Rickettsia felis using integrated computational approaches Frontiers in Veterinary Science Rickettsia felis novel drug targets succinate dehydrogenase in silico screening pharmacokinetics |
| title | Prediction of potential drug targets and key inhibitors (ZINC67974679, ZINC67982856, and ZINC05668040) against Rickettsia felis using integrated computational approaches |
| title_full | Prediction of potential drug targets and key inhibitors (ZINC67974679, ZINC67982856, and ZINC05668040) against Rickettsia felis using integrated computational approaches |
| title_fullStr | Prediction of potential drug targets and key inhibitors (ZINC67974679, ZINC67982856, and ZINC05668040) against Rickettsia felis using integrated computational approaches |
| title_full_unstemmed | Prediction of potential drug targets and key inhibitors (ZINC67974679, ZINC67982856, and ZINC05668040) against Rickettsia felis using integrated computational approaches |
| title_short | Prediction of potential drug targets and key inhibitors (ZINC67974679, ZINC67982856, and ZINC05668040) against Rickettsia felis using integrated computational approaches |
| title_sort | prediction of potential drug targets and key inhibitors zinc67974679 zinc67982856 and zinc05668040 against rickettsia felis using integrated computational approaches |
| topic | Rickettsia felis novel drug targets succinate dehydrogenase in silico screening pharmacokinetics |
| url | https://www.frontiersin.org/articles/10.3389/fvets.2024.1507496/full |
| work_keys_str_mv | AT sudaisrahman predictionofpotentialdrugtargetsandkeyinhibitorszinc67974679zinc67982856andzinc05668040againstrickettsiafelisusingintegratedcomputationalapproaches AT hsienliu predictionofpotentialdrugtargetsandkeyinhibitorszinc67974679zinc67982856andzinc05668040againstrickettsiafelisusingintegratedcomputationalapproaches AT mohibuallahshah predictionofpotentialdrugtargetsandkeyinhibitorszinc67974679zinc67982856andzinc05668040againstrickettsiafelisusingintegratedcomputationalapproaches AT mashalmalmutairi predictionofpotentialdrugtargetsandkeyinhibitorszinc67974679zinc67982856andzinc05668040againstrickettsiafelisusingintegratedcomputationalapproaches AT iramliaqat predictionofpotentialdrugtargetsandkeyinhibitorszinc67974679zinc67982856andzinc05668040againstrickettsiafelisusingintegratedcomputationalapproaches AT tetsuyatanaka predictionofpotentialdrugtargetsandkeyinhibitorszinc67974679zinc67982856andzinc05668040againstrickettsiafelisusingintegratedcomputationalapproaches AT chienchinchen predictionofpotentialdrugtargetsandkeyinhibitorszinc67974679zinc67982856andzinc05668040againstrickettsiafelisusingintegratedcomputationalapproaches AT chienchinchen predictionofpotentialdrugtargetsandkeyinhibitorszinc67974679zinc67982856andzinc05668040againstrickettsiafelisusingintegratedcomputationalapproaches AT chienchinchen predictionofpotentialdrugtargetsandkeyinhibitorszinc67974679zinc67982856andzinc05668040againstrickettsiafelisusingintegratedcomputationalapproaches AT chienchinchen predictionofpotentialdrugtargetsandkeyinhibitorszinc67974679zinc67982856andzinc05668040againstrickettsiafelisusingintegratedcomputationalapproaches AT abdulazizalouffi predictionofpotentialdrugtargetsandkeyinhibitorszinc67974679zinc67982856andzinc05668040againstrickettsiafelisusingintegratedcomputationalapproaches AT abidali predictionofpotentialdrugtargetsandkeyinhibitorszinc67974679zinc67982856andzinc05668040againstrickettsiafelisusingintegratedcomputationalapproaches |