Potentials of cepharanthine and tomatidine as novel LpxC and TLR4 inhibitors to mitigate gut-mediated inflammation in Parkinson's disease: a high-throughput investigation through molecular docking and dynamic simulation.

Gut dysbiosis is strongly implicated in the pathogenesis of Parkinson's disease (PD), where the interaction between bacterial endotoxin lipopolysaccharide (LPS) and human toll-like receptor 4 (TLR4) plays a crucial role. Inhibiting LPS-synthesizing enzyme LpxC and LPS-TLR4 interaction will reduce bacterial load and gut-brain inflammation. Side effects associated with the currently investigated synthetic inhibitors urge the need for effective alternatives. The present study was conducted to identify LpxC and TLR4 inhibitors from phyto-alkaloids, a class well-known for its therapeutic abilities. 505 alkaloids were yielded from the database search, amongst which 314 alkaloids showed gut-blood and blood-brain barrier permeability, and favorable drug-likeness. Site-specific docking of 314 alkaloids yielded 29 and 88 hit ligands for LpxC and TLR4 respectively. Subsequently, the molecular interaction analysis revealed cepharanthine as the most potential dual inhibitor of LpxC and TLR4, followed by tomatidine. Greater affinity, strength, and stability observed in molecular dynamic simulation further strengthened the LpxC and TLR4 inhibition by cepharanthine and tomatidine, with cepharanthine being a more potential TLR4 inhibitor and tomatidine a better LpxC inhibitor. Pharmacokinetic property assessment suggested favorable absorption, distribution, metabolism, and elimination of tomatidine, while the clinical application of cepharanthine for snake bite, leukopenia, and alopecia supports its minimal toxicity. Presenting cepharanthine and tomatidine as dual inhibitors of LpxC and TLR4, the study suggests a plausible multitarget single or combinatorial drug therapy strategy for countering gut dysbiosis and PD. However, preclinical and clinical investigations and improved pharmacokinetics of cepharanthine and tomatidine are warranted to validate our in silico findings.