SOURCE:

Faculty: Pharmaceutical Sciences
Department: Pharmaceutical And Medicinal Chemistry

CONTRIBUTORS:

Ezebuo, F. C.
Uzochukwu, I. C.

ABSTRACT:

Schistosomiasis is aprevalent neglected tropical disease especially in northern Nigeria with high morbidity and mortality. It has shown low activity and resistance in its treatment using praziquantel or oxamniquine. It is important to identify alternative, additional or adjunctive drugs to ensure that praziquantel or oxamniquineresistance does not become a major health concern. Drugs that modulate more than one drug targets are less prone to problem of drug resistance. The aim of the research was to identify approved drugs with possible multi-target inhibitory activities against Schistosoma species. To achieve the aim, the study was designed to:(a) identify schistosoma drug targets using bioinformatic mining;(b) determine binding energies of selected approved drugs against schistosoma drug targets;(c) perform molecular dynamics simulations of targets and target-frontrunner complexes; (d) determine conservation of schistosomal drug targets and human liver enzymes in Drosophila melanogaster; (e) determine longevity and survival rates of D. melanogaster to some of the predicted drugs.Four schistosomal drug targets were obtained through bioinformatics mining. Six hundred and twelve (612) approved drugs including their isomers were selected based on their Molinspiration® bioscore similarities with reference compounds (praziquantel, oxamniquine, auranofin and propylamino-3-hydroxy-buta-1,4-dionyl]-isoleucylproline). The 3-D coordinates of the selected drugs were obtained from ZINC® database. The drug targets and approved drugs were prepared for docking simulations using Molecular Graphics Laboratory Tools-1.5.6 and University of California San Francisco (UCSF) Chimera 1.9. Molecular docking simulations were performed using AutoDockvina®-1.1.2 while molecular dynamics simulations were performed with GROMACS-4.5.5. The binding energies were calculated from the molecular docking simulations and using g_MMPBSA (Molecular Mechanics Poisson-Boltzmann Surface Area).Conservation of selected drug targets and three human liver enzymes (alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase) in D. melanogaster were determined using BLAST search in FlyBase.The use of D. melanogaster as a model organism for antischistosomiasis was investigated by studying their longevity and survival rates as percentage of live flies when treated with three identified possible inhibitors.Tolmetin was predicted as potential multi-target antischistosomal drug with binding energies of -231.064±18.55 and -338.636±36.90 KJ/mol for sulfotransferase and thioredoxin glutathione reductase (TGR) repectively. Also diflunisal was predicted as potential multi-target antischistosomal drug with binding energies of -168.641±20.37 and -290.117±43.80 KJ/mol for sulfotransferase and TGR respectively. Schistosomal glutathione s-transferase and sulfotransferase are not conserved in D. melanogaster. Also, human liver alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase are conserved in D. melanogaster. Longevity and survival rate experiments using D. melanogaster showed100 % survival of the flies in praziquantel, oxytetracycline, haloperidol or vildagliptin within one week of administration. Molecular docking and dynamics simulations indicated that tolmetin and diflunisal are possible inhibitors of schistosomal sulfotransferase and thioredoxin glutathione reductase. Longevity and survival rate experiments using D. melanogaster indicate that praziquantel, oxytetracycline, haloperidol or vildagliptin are safe for the flies within one week of administration. Determination of conservation showed that D. melanogastercan be used for schistosomiasis studies.