ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1630038
Exploring murE protein inhibitors of Tropheryma whipplei through pharmacoinformatic approaches incorporating solubility-enhancing formulation insights
Provisionally accepted
Zarrin Basharat1*
Calvin R. Wei2
Madiha Islam3
Ibrar Ahmed4
Hanan Ogaly5Fatimah A M Al-Zahrani5
Yasir Waheed6
Seil Kim4*- 1Alpha Genomics Private Limited, Islamabad, Pakistan
- 2Shing Huei Group, Taipei, Taiwan
- 3Hazara University, Mansehra, Pakistan
- 4Korea Research Institute of Standards and Science, Daejeon, Republic of Korea
- 5King Khalid University, Abha, Saudi Arabia
- 6NUST, Islamabad, Pakistan
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Tropheryma whipplei, the causative agent of Whipple disease, presents a diagnostic challenge due to its diverse symptomatology, including weight loss, abdominal pain, diarrhea, joint pain, fever, and occasionally neurological manifestations. Its resistance to fluoroquinolones complicates treatment further. Traditional methods for antibiotic susceptibility testing are ineffective as T.whipplei cannot be cultured in axenic media. To address this, we explored potential drug targets within its core genome as no drug targets from this bacterium have been studied so far. murE, a macrolide-resistant enzyme, emerged as a promising candidate exhibiting both resistance and drug target characteristics. We screened over 1,000 lead-like Ayurvedic compounds against the target enzyme UDP-N-acetylmuramyl-tripeptide synthetase and identified three promising candidates:(1) Ergost-5-en-3-ol (3beta,24xi), ( 2) [6]-Gingerdiol 3-monoacetate, and (3) Valtrate. DiffDock and GNINA rescoring yielded consistent binding strength rankings. Molecular dynamics simulations over 100 nanoseconds confirmed stable interactions with these compounds. ADMET analysis indicated low water solubility, but coupling with cyclodextrin SBE-β-CD improved solubility. None of the compounds showed hepatotoxic effects, though Valtrate exhibited AMES toxicity. Based on the favorable properties, we propose scaffold hopping and further in vitro/in vivo studies on [6]-Gingerdiol 3-monoacetate. Our findings offer potential avenues for combating T. whipplei infections, addressing the limitations posed by antibiotic resistance.
Keywords: Tropheryma whipplei, Whipple's disease, Ayurveda, Virtual Screening, MD simulation
Received: 16 May 2025; Accepted: 31 Jul 2025.
Copyright: © 2025 Basharat, Wei, Islam, Ahmed, Ogaly, Al-Zahrani, Waheed and Kim. 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:
Zarrin Basharat, Alpha Genomics Private Limited, Islamabad, Pakistan
Seil Kim, Korea Research Institute of Standards and Science, Daejeon, Republic of Korea
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