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

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.

Childhood diarrhoeal diseases in developing countries

“…Besides, there are pieces of evidence showing that bioinformatics is a very reliable epidemiological tool during disease and antimicrobial resistance surveillance (Bessoff et al, 2013;Gardner and Hall, 2013;Kaiser et al, 2016;Yodmeeklin et al, 2017). Also, with bioinformatics applications, scientists are already discovering new drug targets for the treatment of diarrhoeal diseases (Allan, 2014;Ugboko et al, 2019).…”

In Silico Investigation of First-Pass Effect on Selected Small Molecule Excipients and Structural Dynamics of P-glycoprotein

“…The dynamics of P-gp structure (PDB: 6C0V, chain A) was investigated according to the method of Ugboko et al 25 at pH 7.5. Briefly, from the crystal structure (X-ray structure), PDBFixer implemented in OpenMM v7.3 26 on CPU platform was used to fix the protein.…”

Antibiofilm agents with therapeutic potential against enteroaggregative Escherichia coli

“…https://www.drugbank.ca/drugs/DB01087, which is active against gametocytes as well as recalcitrant parasitic forms of malaria, and therefore useful for preventing vivax and ovale relapse [70]. None of these four compounds has any previously documented antibacterial activity (in vivo or in vitro) against Gram negative bacteria, however, Ugboko et al (2019) in an in silico screen and analysis of broad-spectrum molecular targets and lead compounds for potential anti-diarrhoea agents reported MMV687800 as one of the compounds with predicted activity against potential targets for diarrhoea disease among twenty five other compounds [71]. Low et al (2017) in screen to identify TB active compounds against nontuberculous Mycobacterium additionally retrieved MMV687800 as an M. avium-specific main hits among five other MMV compounds [72] and Hennessey et al (2018) also reported MMV687800 among seven MMV compounds as an inhibitor with dual efficacy against Giardia lamblia and Cryptosporidium parvum in a pathogen box screen [73].…”