Discovery of Cucurbita maxima compounds as Schistosoma mansoni and Schistosoma haematobium inhibitors.

Abstract

Over 200 million people worldwide suffer from schistosomiasis, a disease usually associated with poverty and poor sanitation. A single drug, praziquantel (PZQ), has been used by the medical community since the 1970s. The emerging evidence of resistance of the Schistosoma parasite to praziquantel, and the drug's ineffectiveness against juvenile stages of the parasite, calls for alternative drug. The exploration of the inhibition potential of compounds from Cucurbita maxima using molecular docking studies on Schistosoma mansoni purine nucleoside phosphorylase (SmPNP) and Schistosoma haematobium 28-kDa glutathione S-transferase (Sh28kDaGST) was done. Following molecular docking studies and analysis of the active sites, the primary amino acids that were observed and shown to be involved in the SmPNP-ligand interaction are CYS 33, ARG 86, HIS 88, TYR 90, ALA 118, ALA 119, PRO 200, TYR 202, GLU 203, VAL 219, MET 221, THR 244, ASN 245, PRO 257 and HIS 259. For the Sh28dKa-ligand interaction, the primary amino acids were PHE 11, ARG 16, TRP 41, LEU 53, GLU 70 and SER 71. Momordicoside I aglycone binds to SmPNP HIS88 with the lowest binding energy of -7.9kcal/mol. Balsaminoside B binds to Sh28kDaGST with a binding energy of −7.6kcal/mol by hydrogen bond interaction with TRP 41, LEU 53 and SER 71. The anti-schistosomal activity of C. maxima seeds extract alone and in combination with PZQ on Schistosoma mansoni-infected mice and were also done. The parasites were sampled from the Mupfure River in the Mashonaland East province of Zimbabwe from three different village sites namely Chikanza, Matimure and Mwedziwandira. Infection of guinea pigs with Schistosoma haematobium was attempted. Unfortunately, the infection in the guinea pigs was unsuccessful. Results indicate a statistically significant reduction in granuloma size in the C. maxima extract +praziquantel treated group, with a 13,24% margin compared to the C. maxima seeds extracts treated group. Treatment by C. maxima seeds extract and C. maxima seeds extract + PZQ significantly reduced the egg count in intestines and live (p=0.00; p=0.00 & p=0.00), respectively. There was no significant difference in the effect of the village sites from where the parasites were sampled (p>0.05). The anti-schistosomal effect of C. maxima extracts and their synergistic effects when in combination with praziquantel were observed. In addition to providing a predictive model for interactions between C. maxima ligands, SmPNP and Sh28kDaGST, the in vivo work validated the in silco findings and confirmed that C. maxima does have antischistosomal properties. We propose that as future work, in vitro studies on the target proteins be carried out to elucidate the mechanism of action of the C. maxima plant. We also recommend performing selectivity tests of the best-performing compounds on the target proteins. Overall, our study lays a crucial foundation in the development of a new drug against schistosomiasis and we recommend that C. maxima seeds and their combination with praziquantel be considered as candidates for the development of a new drug against schistosomiasis.