Computer-aided drug design and biological evaluation of novel anti-viral agents.

Vlachakis, Dimitrios P. ORCID: https://orcid.org/0000-0003-1823-6102 2006. Computer-aided drug design and biological evaluation of novel anti-viral agents. PhD Thesis, Cardiff University.

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Abstract

In this thesis is presented a description of studies concerning the molecular modelling and biological evaluation of a set of novel antiviral agents for the helicase and polymerase proteins of Flaviviridae. Viruses in this family are enveloped, have positive-sense RNA and are responsible for a variety of life threatening diseases. To date neither specific antiviral treatments exist nor are there any vaccines available for Flaviviridae infection. Thus there is an urgent need for new therapies. The ultimate aim of this project was to design a coordinated in silico in vitro protocol for the design and evaluation of novel Flaviviridae inhibitors. That was achieved initially by establishing the three-dimensional structures of various Flaviviridae members by homology-based molecular modelling. In continuation, a set of small compound libraries was designed using a de novo structure-based drug design approach. Those compounds were screened in silico with the aid of molecular docking and a set of scoring algorithms. The best candidates were chosen to be chemically synthesised not part of this thesis. The genes of Hepatitis C and Dengue helicases as well as the Dengue NS3 domain helicase and protease were cloned in expression vectors and the proteins were produced and purified. A novel biological assay was then established for the Hepatitis C helicase in order to evaluate the potency of the designed inhibitors in vitro. An attempt was finally made to feedback the computer model using the biological activity data of those compounds, in order to improve the cooperation levels between the in silico and the in vitro parts of this research.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Pharmacy
Subjects:	R Medicine > RM Therapeutics. Pharmacology
ISBN:	9781303176814
Date of First Compliant Deposit:	30 March 2016
Last Modified:	25 Oct 2022 08:44
URI:	https://orca.cardiff.ac.uk/id/eprint/54324

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