Quantitative structure activity relationship (QSAR) modeling using high-throughput screening (HTS) data enables the development of predictive models for in silico screening. A cheminformatics framework termed BCL::ChemInfo was developed to establish QSAR modeling for application in drug discovery. Its prediction performance was evaluated through an extensive benchmark study assessing curated datasets from PubChem. BCL::ChemInfo was applied to identify novel pathway specific inhibitors for β-hematin crystallization in Plasmodium falciparum associated with Malaria. The resulting models achieved an experimental enrichment of 44 fold compared to the initial HTS hit rate of 0.37% for compounds based on a concentration threshold of 70µM. Sampled from these identified hit compounds, 15 out of 17 molecules were confirmed to perturb the hemozoin formation pathway in P. falciparum. Another research study involved the identification of novel specific allosteric modulators for mGlu5 acting on a distinct site related to CPPHA binding. From a compound library of over four million commercially available compounds five compounds where identified through in silico screening and experimentally validated to bind exclusively to this novel site. BCL::ChemInfo was also adapted to predict small molecule properties such as the wateroctanol partition coefficient (LogP). The resulting prediction accuracy surpassed the current gold standard method XLogP.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-07262014-191812 |
| Date | 28 July 2014 |
| Creators | Butkiewicz, Mariusz |
| Contributors | Clare M. McCabe, Jens Meiler, Brian O. Bachmann, David W. Wright |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-07262014-191812/ |
| Rights | restrictsix, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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