In Silico Screening and Analysis of Broad-Spectrum Molecular Targets and Lead Compounds for Diarrhea Therapy

Author:

Ugboko Harriet U1ORCID,Nwinyi Obinna C1,Oranusi Solomon U1,Fatoki Toluwase H2,Akinduti Paul A1,Enibukun Jesupemi M3

Affiliation:

1. Microbiology Research Unit, Department of Biological Sciences, Covenant University, Ota, Nigeria

2. Enzyme Biotechnology and Pharmaceutics Research Unit, Department of Biochemistry, The Federal University of Technology, Akure, Nigeria

3. Molecular Biology and Environmental Microbiology Research Unit, Department of Microbiology, The Federal University of Technology, Akure, Nigeria

Abstract

Diarrhoeal disease kills about 1.5 million human beings per year across the continents. The enterotoxigenic Escherichia coli (ETEC) pathotype has been noted as a major cause of diarrheal disease in human and livestock. The aim of this study is to identify broad-spectrum molecular targets in bacteria and broad-spectrum lead compounds (functional inhibitors) with high efficacy and no significant adverse implication on human systems, in relevance to diarrhea therapy through computational approaches which include phylogenetics, target prediction, molecular docking, and molecular flexibility dynamic simulations. Three molecular target genes, murA, dxr, and DnaE, which code for uridine diphosphate- N-acetylglucosamine-1-carboxyvinyltransferase, 1-deoxy-D-xylulose-5-phosphate reductoisomerase, and deoxyribonucleic acid polymerase III alpha subunit, respectively, were found to be highly conserved in 7 diarrhea-causing microbes. In addition, 21 potential compounds identified showed varied degree of affinity to these enzymes. At free energy cutoff of −8.0 kcal/mol, the highest effective molecular target was DNA polymerase III alpha subunit (PDB ID: 4JOM) followed by UDP- N-acetylglucosamine-1-carboxyvinyltransferase (PDB ID: 5UJS), and 1-deoxy-D-xylulose-5-phosphate reductoisomerase (PDB ID: 1ONN), while the highest effective lead compound was N-coeleneterazine followed by amphotericin B, MMV010576, MMV687800, MMV028694, azithromycin, and diphenoxylate. The flexibility dynamics of DNA polymerase III alpha subunit unraveled the atomic fluctuation which potentially implicated Asp593 as unstable active site amino acid residue. In conclusion, bacteria DnaE gene or its protein is a highly promising molecular target for the next generation of antibacterial drugs of the class of N-coeleneterazine.

Publisher

SAGE Publications

Subject

Applied Mathematics,Computational Mathematics,Computer Science Applications,Molecular Biology,Biochemistry

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