Identification and structural bioinformatics of druggable proteins in schistosoma species
Loading...
Date
2018
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
University of Zululand
Abstract
Schistosomiasis is a debilitating disease caused by a parasitic flatworm found in freshwater. After malaria, this disease is the second most prevalent disease in Africa and is endemic in both tropical and sub-tropical regions of the world. Morbidity and mortality attributed to this disease are very high with about 240 million people infected, 800 million persons at risk of the infection and an approximately 280,000 deaths occurring annually. With the exponential increase in morbidity and mortality resulting from Schistosomiasis, there is an urgent need for the development of new drug since studies have shown that schistosomes are becoming resistant to the widely accepted first-line drug-of-choice Praziquantel (PZQ). Therefore, the present study describes the exploration of broad-spectrum therapeutic potentials of Antimicrobial peptides (AMPs) in the design of alternative anti-schistosomal treatment regimen. AMPs are natural antibiotics produced by all living species; they have multifunctional properties and are currently explored as a vital source for the development of new drugs. The use of therapeutic peptides in various disorder treatment has been receiving significant and great attention in recent years. In this study, six putative AMPs (TAK1-TAK6) were identified to possess very strong anti-schistosomal capabilities using Hidden Markov Model. Added to this, glycosyltransferase and axonemal dynein intermediate chain schistosomal proteins were identified using in silico methods as vital proteins for the survival of the parasite in the host. The 3D structures of the AMPs and the proteins were modelled using the I-TASSER, while PatchDock was employed to ascertain the interaction between these schistosome proteins and the AMPs. Results obtained show that the putative AMPs have good binding affinity to the schistosomal proteins. More so, TAK3 and TAK6 showed highest binding affinities to glycosyltransferase and Axonemal dynein intermediate chain respectively. Site-directed mutagenesis studies based on the putative anti-schistosomal AMPs was carried out to increase
iii
their biological activities; homology modelling of the mutated AMPs using I-TASSER showed that they are identical to the parental AMPs. More so, results from molecular docking using PatchDock showed that these mutated AMPs are capable of interacting with the schistosome proteins. In conclusion, results suggest that these peptides maybe potential “drug leads” in the design and development of alternative schistosomal therapy and could as well prove to be effective against PZQ-resistant schistosome strains, based on the strong interactions between both the AMPs (Parental and Mutated) and the schistosomal proteins.
Description
A dissertation submitted to the Department of Biochemistry and Microbiology in fulfilment of the requirements for Master of Biochemistry Degree in the Faculty of Science and Agriculture at the University of Zululand, 2018.
Keywords
structural bioinformatics, druggable proteins, schistosoma species