Peristera, Ourania. QSAR at the estrogen and mineralocorticoid receptors. 2010, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_9050
Nuclear receptors regulate biological functions such as cell growth and differentiation, metabolic processes, reproduction and development, intracellular signaling and can be involved in carcinogenesis through the control of gene expression. Chemicals that disrupt the endocrine system interfere with the function of nuclear receptors, alter their functions and cause adverse health effects.
In this thesis, the development and validation of three-dimensional in silico models for the mineralocorticoid and the estrogen receptors _, both belonging to the nuclear receptor superfamily, are presented. These models aim at the screening of drug candidates for mineralocorticoid and estrogen _ activity as well as of environmental chemicals for potential endocrine-disrupting activity.
Different in silico tools and protocols were used to quantify receptor-ligand interactions. Those included, molecular dynamics simulations allowing gaining an insight into the dynamical character of the protein-ligand interactions. Multi-dimensional QSAR models were built, using two different technologies, and validated by employing external validation sets, and scramble tests. The models have been added to the VirtualToxLab - a technology for the in silico identification of the toxic (endocrine-disrupting) potential of drugs and environmental chemicals.
A Cambridge Structural database (CSD) search was performed in order to obtain an insight on the existence and the nature of intermolecular interactions involving halogen atoms. Both geometry and topology of such interactions were analyzed and quantified. An algorithm was developed to ensure the high-throughput analysis of the 3D structures, which were used as input for the QSAR study and the VirtualToxLab. The input for this program is the coordinate file and the name of the compound, and the output is a flag (verified/not verified) along with detailed information about this decision file.
The benefit of this thesis on the society, is that an in silico approach can be used, which is faster and less expensive when comparing to in vitro and in vivo experiments. Such an approach may contribute to the well being of man and wildlife since no chemicals are used and the natural resources are retained.
|Committee Members:||Odermatt, Alex|
|Faculties and Departments:||05 Faculty of Science > Departement Chemie > Chemie > Computational Toxicology (Vedani)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||225 Bl.|
|Last Modified:||30 Jun 2016 10:41|
|Deposited On:||02 Jul 2010 06:45|
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