Abstract
Praziquantel (PZQ) has been the World Health Organizations (WHO) recommended schistosomiasis treatment for the greater part of 5 decades. PZQ resistant Schistosoma spp. have been documented in previous years (1994 – 2014), giving rise to the requirement for effective alternatives. This study investigated the effect of dynarrestin on the potential drug target, Schistosoma mansoni Axonemal Dynein Intermediate Chain protein (SmAxDynIC). The protein functions in ciliary and flagella beating of the schistosome worm, hence the inhibition of this protein could prove detrimental to parasite motility, disrupting its life cycle. Molecular Dynamic (MD) simulations and post-MD analyses ascertained the computational inhibitory characteristics of dynarrestin on the SmAxDynIC protein, while interaction between the SmAxDynIC protein and dynarrestin was confirmed through UV/Vis, FTIR and Raman spectroscopy. The generation and screening of the dynarrestin pharmacophore revealed structural analogue inhibitors as ‘lead’ compounds against schistosomiasis. Increased average values for RMSD (3.12 Å to 3.69 Å), RMSF (5.93 Å to 12.07 Å) and decreased SASA (7685.77 Å to 7662.17 Å) and RoG (15.62 Å to 15.42 Å) values indicated native protein conformation destabilisation post-interaction of dynarrestin with the SmAxDynIC protein. Three additional ligands were identified using the pharmacophore, and their employment for in vitro testing on various schistosomal cell lines in future interaction studies is recommended.
Keywords: SmAxDynIC, Praziquantel, Dynarrestin, MD simulations, Pharmacophore.