The methyltransferase and helicase enzymes as therapeutic targets of Zika virus : a bio- computational analysis of interactions with potential inhibitors.
Year: 2019
Type: dissertation
Abstract: The rampant Zika virus has received worldwide attention after becoming a global crisis following the \nBrazilian epidemic in 2015. From an obscure and neglected pathogen, Zika virus is now a notorious \nvirus associated with neurological disorders in infants and adults. Since 2016, the rapid research \nresponse from the global scientific community have led to the discovery of numerous potential small \nmolecule inhibitors and vaccines against the Zika virus. Although, in spite of this massive research \ninitiative, there is still no effective antiviral nor vaccine that has made it out of clinical trials. \nThe design and development of new chemical entities demands excessive cost, time and resources. \nTherefore, this study applies computer-aided drug design techniques, which accelerates the rational \ndrug design process. Computational approaches including molecular docking, virtual screening, \nmolecular modeling and molecular dynamics facilitate the filtration of large databases of compounds \nto sift out potential lead compounds. \nFurthermore, research has dedicated several resources toward FDA-approved drug repurposing. \nGenerally, drugs have similar effects on viruses of the same family; hence drugs that have previously \nbeen effective in treating other flaviviruses, such as Dengue virus and West Nile virus, are being \ntested for its potential inhibition of Zika virus. However, the ability of these drugs to pass the bloodbrain \nbarrier to treat infected neurons poses a challenge to anti-Zika virus drug discovery. This study \nproposes innovative strategies to design drugs that are capable of passing the blood-brain barrier, and \nto be able to use drugs that are impermeable via drug delivery mechanisms. This study also assesses \nthe bioavailability and blood-brain barrier permeability of screened drugs to scrutinize the list of \npotential Zika virus inhibitors. \nApart from identifying potential inhibitors, understanding the structural dynamics of viral targets and \nmolecular mechanisms underlying potential inhibition of the virus is imperative. This study explores \nthe structural and molecular dynamics of key targets of the Zika virus, the NS3 helicase and the NS5 \nmethyltransferase enzymes, using computational approaches mentioned above and several others \nelaborated in this thesis. These computational methods also allowed the identification of precise \ninteractions, amino acid residues, inhibitory mechanisms and pharmacophoric features involved in \nbinding of lead compounds to these enzymes. \nIX \nChapter 4 represents the first study of this thesis, which presents a concise literature background of \nZika virus and identifies blood-brain barrier permeability as a core challenge in anti-Zika virus drug \ndevelopment. This study also provides approaches that may enable researchers to create effective \nanti-Zika virus drugs. \nChapter 5 is the subsequent study of this thesis, which applies molecular dynamics to comparatively \ninvestigate the mechanism of inhibition and binding mode of two potential inhibitors, sinefungin and \ncompound 5, to the NS5 methyltransferase. The specific pharmacophoric moieties of the most stable \ninhibitor are also identified in this study. \nChapter 6 is the final study of this thesis, which examines the structural dynamics of the Zika virus \nNS3 helicase enzyme upon binding of ATPase inhibitor and flavivirus lead compound, resveratrol, \nand reports the key interactions and amino acid residues of the NS3 helicase that contribute highly to \nbinding of resveratrol. \nThis thesis presents an all-inclusive in silico assessment to advance research in drug design and \ndevelopment of Zika virus inhibitors, thus providing a greater understanding of the structural \ndynamics that occur in unbound and inhibitor-bound Zika virus target enzymes. Therefore, the \nconstituents of this thesis are considered an essential platform in the progression of research toward \nanti-ZIKV drug design, discovery and delivery against Zika virus.
Author: Nikita Devnarain
Language: English
Subfield: Drug Discovery
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3003200252