The methyltransferase and helicase enzymes as therapeutic targets of Zika virus : a bio- computational analysis of interactions with potential inhibitors.

Abstract

The rampant Zika virus has received worldwide attention after becoming a global crisis following the Brazilian epidemic in 2015. From an obscure and neglected pathogen, Zika virus is now a notorious virus associated with neurological disorders in infants and adults. Since 2016, the rapid research response from the global scientific community have led to the discovery of numerous potential small molecule inhibitors and vaccines against the Zika virus. Although, in spite of this massive research initiative, there is still no effective antiviral nor vaccine that has made it out of clinical trials. The design and development of new chemical entities demands excessive cost, time and resources. Therefore, this study applies computer-aided drug design techniques, which accelerates the rational drug design process. Computational approaches including molecular docking, virtual screening, molecular modeling and molecular dynamics facilitate the filtration of large databases of compounds to sift out potential lead compounds. Furthermore, research has dedicated several resources toward FDA-approved drug repurposing. Generally, drugs have similar effects on viruses of the same family; hence drugs that have previously been effective in treating other flaviviruses, such as Dengue virus and West Nile virus, are being tested for its potential inhibition of Zika virus. However, the ability of these drugs to pass the bloodbrain barrier to treat infected neurons poses a challenge to anti-Zika virus drug discovery. This study proposes innovative strategies to design drugs that are capable of passing the blood-brain barrier, and to be able to use drugs that are impermeable via drug delivery mechanisms. This study also assesses the bioavailability and blood-brain barrier permeability of screened drugs to scrutinize the list of potential Zika virus inhibitors. Apart from identifying potential inhibitors, understanding the structural dynamics of viral targets and molecular mechanisms underlying potential inhibition of the virus is imperative. This study explores the structural and molecular dynamics of key targets of the Zika virus, the NS3 helicase and the NS5 methyltransferase enzymes, using computational approaches mentioned above and several others elaborated in this thesis. These computational methods also allowed the identification of precise interactions, amino acid residues, inhibitory mechanisms and pharmacophoric features involved in binding of lead compounds to these enzymes. IX Chapter 4 represents the first study of this thesis, which presents a concise literature background of Zika virus and identifies blood-brain barrier permeability as a core challenge in anti-Zika virus drug development. This study also provides approaches that may enable researchers to create effective anti-Zika virus drugs. Chapter 5 is the subsequent study of this thesis, which applies molecular dynamics to comparatively investigate the mechanism of inhibition and binding mode of two potential inhibitors, sinefungin and compound 5, to the NS5 methyltransferase. The specific pharmacophoric moieties of the most stable inhibitor are also identified in this study. Chapter 6 is the final study of this thesis, which examines the structural dynamics of the Zika virus NS3 helicase enzyme upon binding of ATPase inhibitor and flavivirus lead compound, resveratrol, and reports the key interactions and amino acid residues of the NS3 helicase that contribute highly to binding of resveratrol. This thesis presents an all-inclusive in silico assessment to advance research in drug design and development of Zika virus inhibitors, thus providing a greater understanding of the structural dynamics that occur in unbound and inhibitor-bound Zika virus target enzymes. Therefore, the constituents of this thesis are considered an essential platform in the progression of research toward anti-ZIKV drug design, discovery and delivery against Zika virus.