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Computer aided design and synthesis of new anticancer and antiviral compounds.

Barbera, Maria Chiara. 2007. Computer aided design and synthesis of new anticancer and antiviral compounds. PhD Thesis, Cardiff University.

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Abstract

Among all the recent advances in different but complementary scientific fields, the impressive progress and development of more powerful computational techniques play a key role in drug design. Computer aided design has become indispensable and complimentary to traditional and modern approaches by guiding medicinal chemists to improve and speed the discovery, design, synthesis and optimization of novel active molecules. The present study has been focused on the design of protein-protein and protein-DNA interacting small molecules inhibitors with the support of computational methods. An accurate investigation of protein-protein and protein-inhibitor interactions present in the microtubules complex has been carried out by means of different computational methods: QSAR analysis, Molecular Docking, Flexible Alignment and Molecular Dynamics Simulation. The information derived from these computational studies have guided the design and chemical synthesis of new arylthioindole derivates as small molecule inhibitors of tubulin polymerization. Based on structural data and synthesis work previously carried out, two distinct databases of potential small molecule inhibitors of HCV helicase/NTPase enzyme have been generated and evaluated by computational methods, thus guiding the selection of several structures. Successfully synthesised compounds have been sent for biological testing via an HCV replicon assay: some of them have shown interesting and promising inhibitory activity by blocking the virus replication in vitro. The refined homology model of the antiapoptotic protein Bcl-2 has led to the generation and virtual screening of small combinatorial libraries of drug-like compounds, carried out by means of different computational applications (pharmacophore and conformational searches, molecular docking, molecular dynamics) to find non-peptidic inhibitors of Bcl-2. By means of various molecular modeling applications (pharmacophore and conformational search, generation of combinatorial libraries, molecular docking, molecular dynamics), structurally diverse compounds have been designed and virtually screened following the investigation, anisomycin derivates have resulted to be potential candidates as small molecule inhibitors of Mdm2/p53 complex.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
ISBN: 9781303176852
Date of First Compliant Deposit: 30 March 2016
Last Modified: 09 Jan 2018 20:33
URI: http://orca-mwe.cf.ac.uk/id/eprint/54328

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