Abstract
Human schistosomiasis has heavily plagued the destitute of various tropical and sub-tropical countries of the world, particularly in sub-Saharan Africa and South America, with devastating effects in various health and economic areas. Globally, the burden of schistosomiasis has been controlled by using a single chemotherapeutic drug, Praziquantel. However, the drug has recently displayed various shortcomings, including its inability to destroy juvenile schistosome worms, as well as drug resistance in response to its extensive use. This has prompted efforts concentrated on the discovery and design of new anti-schistosomal drugs. In this study, biophysical and in silico techniques were used to elucidate the structural binding and interaction between the S. mansoni heat shock protein 60 (SmHsp60) and epolactaene-based inhibitors. The upregulation of heat shock proteins in the schistosome lifecycle is significant in overcoming the proteotoxic environment experienced within the human host. Through the creation of SmHsp60 complexes with pharmacophore-derived inhibitors, molecular dynamic (MD) simulations have been performed. Post-MD analyses of the trajectories indicated various energetic, structural, and conformational changes, as well as the identity of pertinent Aspartic residues involved in the interaction with the inhibitors. Our in silico results further showed that inhibitor 2 and inhibitor 3 exhibited enhanced inhibitory activity against SmHsp60, thus suggesting their potential as “lead compounds” in the design of a new anti-schistosomal drug. This observation was supported by pharmacokinetic analysis of the compounds against the positive control, Praziquntel. Despite incomplete purification observed, results from biophysical characterization using Raman spectroscopy and FT-IR spectroscopy divulged preliminary data on the secondary structural elements present within the SmHsp60-SBD protein. This data, although inconclusive due to the purification failure can be used as a starting point for studying and structurally characterizing SmHsp60-SBD following successful rounds of purification.