The in silico investigation of pharmacological targets of the zika virus : insights into the structural characteristics of the NS5 and NS3 proteins from atomistic molecular simulations.
Loading...
Date
2017
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
The re-emerging Zika virus has evolved into a catastrophic epidemic during the past year, with an
estimated 1.5 million reported cases of Zika infections worldwide, since the 2015 outbreak in Brazil.
The virus has received considerable attention during 2016 with a flood of new discoveries, from
evolving modes of viral transmission to viral-linked neurological disorders, unique specificity to host
cells and increasing mutation rates. However, prior to the devastating 2015 outbreak in Brazil, the
virus was classified as a neglected pathogen similar to Dengue and the West Nile virus.
Despite the wide-scale research initiative, there is still no cure for the virus. There are currently
vaccine clinical trials that are on-going but there has not been a breakthrough with regard to small
molecule inhibitors. A lot of experimental resources have been allocated to repuposing FDA-approved
drugs as possible inhibitors, however, even some of the most potent flavivirus inhibitors have adverse
toxic effects. The first crystal structure of the zika virus was released in May 2016 and since then, six
viral protein structures have been made available. Due to this lack in structural information, there is
little known regarding the structural dynamics, active binding sites and the mechanism of inhibition of
ZIKV enzymes.
This study delves into the structural characteristics of three of the most crucial enzymatic targets of
the zika virus, the NS5 RNA-dependent RNA polymerase and Methyltransferase as well as the NS3
Helicase. With emerging diseases, such as ZIKV, computational techniques including molecular
modeling and docking, virtual screening and molecular dynamic simulations have allowed chemists to
screen millions of compounds and thus funnel out possible lead drugs. These in silico approaches
have warranted Computer-Aided Drug Design as a cost-effective strategy to fast track the drug
discovery process.
The The above techniques, amongst numerous other computational tools were employed in this study to
provide insights into conformational changes that elucidate potential inhibitory mechanisms, active
site identification and characterization and pharmacophoric features leading to promising small
molecule inhibitor cadidates.
The first study (Chapter 4), provided a comprehensive review on potential host/viral targets as well as
provided a concise route map depicting the steps taken toward identifying potential inhibitors of drug targets when no crystal structure is available. A homology model case study, of the NS5 viral protein,
was also demonstrated.
The second study (Chapter 5) used the validated NS5 homology model to investigate the active sites
at both the RNA-dependent RNA polymerase and Methyltransferase domains and subsequently
employ a generated pharmacophore model to screen for potential inhibitors.
Chapter 6 reports the third study, which investigates the structural dynamics and in turn, the possible
mechanism of inhibition of the ZIKV NS3 Helicase enzyme when bound to ATP-competitive
inhibitor, NITD008. The study also provides insight on the binding mode at the ATPase active site,
thus assisting in the design of effective inhibitors against this detrimental viral target.
Chapter 7 maps out the binding landscape of the ATPase and ssRNA site by demonstrating the
chemical characteristics of potent flavivirus lead compounds, Lapachol, HMC-HO1α and Ivermectin
at the respective NS3 Helicase binding sites.
This study offers a comprehensive in silico perspective to fill the gap in drug design research against
the Zika virus, thus giving insights toward the structural characteristics of pivotal targets and
describing promising drug candidates. To this end, the work presented in this study is considered to be
a fundamental platform in the advancements of research toward targeted drug design/delivery against
ZIKV.
Description
Doctor of Philosophy in Pharmacological Science. University of KwaZulu-Natal, Durban 2017.
Keywords
Zika virus infection--Epidemiology., Virology (Zika virus).