Investigating Tropheryma whipplei murE protein inhibitors using pharmacoinformatic techniques that include formulation insights that improve solubility

Abstract

Weight loss, diarrhea, joint pain, fever, and possibly neurological symptoms are just a few of the symptoms that make diagnosing Tropheryma whipplei, the causative agent of Whipple illness, difficult. Treatment is made much more difficult by its resistance to fluoroquinolones. Because Tropheryma whipplei cannot be cultivated on axenic medium, conventional techniques for assessing antibiotic susceptibility are unsuccessful. Since no drug targets from this bacterium have been investigated to far, we investigated possible drug targets inside its core genome in order to address this. A potential candidate that has both resistance and drug target features is murE, an enzyme that is resistant to macrolides. Three interesting candidates were found after screening more than 1,000 lead-like Ayurvedic compounds against the target enzyme UDP-N-acetylmuramyl-tripeptide synthetase: (1) Ergost-5-en-3-ol (3beta,24xi), (2) [6]-Gingerdiol 3-monoacetate, and (3) Valtrate. Consistent binding strength rankings were obtained using DiffDock and GNINA rescoring. Stable interactions with these chemicals were established by molecular dynamics simulations conducted over a period of 100 nanoseconds.
Low water solubility was found by ADMET analysis; however, solubility was enhanced by coupling with cyclodextrin SBE-β-CD. Valtrate had AMES toxicity, while none of the other chemicals shown hepatotoxic effects. Considering the positive

characteristics, we suggest more in vitro/in vivo research on [6]-Gingerdiol 3-monoacetate as well as scaffold hopping. Our research addresses the constraints caused by antibiotic resistance and provides possible strategies for preventing T. whipplei infections.