Paraherquamides – A new hope and great expectations of anthelmintic agents: Computational studies

Nematode infections impose a significant health and economic burden, particularly as parasites develop resistance to existing treatments and evade host defenses. This study explores the efficacy of 48 paraherquamide analogs, a class of polycyclic spiro-oxindole alkaloids with unique structural features, as potential anthelmintic agents. Employing advanced computational methods, including molecular docking, MM-GBSA, and molecular dynamics simulations, we assessed the interaction of these analogs with the Ls-AchBP receptor, a model for nematode neurotransmission. Among the analogs studied, Paraherquamide K, Mangrovamide A, and Chrysogenamide A showed comparable docking and MM-GBSA scores to the native antagonist. Notably, their binding interactions exhibited slight distinction attributed to structural differences, such as the absence of a di-oxygenated 7-membered ring. Additionally, these analogs demonstrated robust binding stability in the molecular dynamic simulation studies and favorable pharmacokinetic properties in our in-silico ADME assessment. The insights gained from the study highlight the potential of these analogs as a basis for developing new therapeutics for nematode infections. The promising results from this computational analysis set the stage for subsequent in-vivo validations and pre-clinical studies, contributing to the arsenal against parasitic resistance.