Structure-based drug design of sanguinarine derivatives targeting Babesia microti lactate dehydrogenase through...

Babesia microti is a tick-borne apicomplexan parasite of emerging public health importance, particularly in the northeastern United States. Current medications (e.g., atovaquone, azithromycin, clindamycin, and quinine) display limited efficacy and frequent adverse effects, underscoring the urgent need for safer and more potent therapies. In this study, we harnessed a computational drug design pipeline to develop novel sanguinarine derivatives targeting B. microti lactate dehydrogenase (BmLDH)-an essential enzyme for parasite metabolism. We first modified the sanguinarine scaffold to create eight derivatives, followed by structural geometry optimization in Gaussian, molecular docking, and Uni-GBSA scoring to identify top binders. Next, ADMET and drug-likeness analyses demonstrated that these derivatives met essential pharmacokinetic criteria. To further characterize these compounds, DFT calculations were performed to elucidate key electronic and quantum chemical descriptors such as HOMO-LUMO energies, ionization potentials, electron affinities, and electrophilicity indices. The molecular docking docking study reveals Ligand 02 and 04 showed highest affinity with -10.2 and -10.4 kcal mol respectively than the reference compound (-6.60 kcal/mol). Additionally, the Uni-GBSA score also support the binding strength of our selected ligands. Finally, MD simulations revealed stable binding performance of the selected three complexes (Ligand 02, 04, and standard/Diminazene), as evidenced by RMSD, RMSF, Rg, MM-PBSA, PCA, and DCCM. Two derivatives (ligands 02 and 04) showed notably high binding affinities and robust dynamic stability, surpassing the standard diminazene in key metrics. These findings highlight the potential clinical impact of modified sanguinarine derivatives-offering a compelling alternative to current treatments constrained by limited efficacy and adverse effects. This in silico study confirms that our investigated molecules may provide a new opportunity for discovering anti-parasitic drugs against Babesia microti. However, further experimental validation and clinical development are required.