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Title: In silico study to understand the factors which are important for the rational design of novel inhibitors of dUTPase, an antimalarial drug target
Author: Schipani, Alessandro
ISNI:       0000 0004 2750 7741
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2007
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Inhibition of deoxyuridine triphosphate dUTPase, a ubiquitous enzyme and 'first line' of defence against misincorporation of uracil into DNA, is lethal in E. coll, S. cerevisiae and is also probably in a variety of other organisms including, Plasmodium spp., the causative agent of malaria. dUTPase is a potential chemotherapeutic target. An assortment of molecular modelling tools was used to take advantage of the available structural information to identify differences between the human and protozoan dUTPase enzymes. A major objective of this study was to develop, rationally, the available lead compounds into antimalarial drug candidates. Starting from the crystal structure of a cyclic nucleoside derivative bound to P. falciparum dUTPase, structural models for the interaction of a library of analogues with the dUTPase receptor were generated by automated computational docking. The obtained complexes were evaluated for their consistency using quantitative structure-activity relationship analysis. A comparison between the calculated interaction free energies and experimental biological activities was also made. All the possible interactions of the investigated compounds at the active site and probable ligand binding conformations provided an improved basis for structure-based rational ligand design. Based on docking results, a successful R2 0.80 model for prediction of binding affinities was developed using the linear interaction energy method LIE. In addition, three-dimensional Quantitative Structure-Activity Relationship studies 3D-QSAR generated using the CoMFA methodology yielded highly predictive models R2 0.99 and q2 0.74. Extensive use of this set of molecular modelling methodologies docking, GRID, LIE, 3D-QSAR has allowed for the development of models, which were employed successfully to introduce the available structural information early into the development of antimalarial drugs. This has resulted design of new inhibitors and has opened up a variety of new chemistry projects. In addition, some work was carried out for the development of a predictive in silico model Volsurf for the passive blood brain barrier BBB permeation of compounds.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available