Stratagems for effective function evaluation in computational chemistry
In recent years, the potential benefits of high-throughput virtual screening to the drug discovery community have been recognized, bringing an increase in the number of tools developed for this purpose. These programs have to process large quantities of data, searching for an optimal solution in a v...
| Hlavní autoři: | , |
|---|---|
| Další autoři: | |
| Médium: | Diplomová práce |
| Jazyk: | English |
| Vydáno: |
2010
|
| Témata: |
| _version_ | 1826283279222833152 |
|---|---|
| author | Skone, G Gwyn Skone |
| author2 | Cameron, S |
| author_facet | Cameron, S Skone, G Gwyn Skone |
| author_sort | Skone, G |
| collection | OXFORD |
| description | In recent years, the potential benefits of high-throughput virtual screening to the drug discovery community have been recognized, bringing an increase in the number of tools developed for this purpose. These programs have to process large quantities of data, searching for an optimal solution in a vast combinatorial range. This is particularly the case for protein-ligand docking, since proteins are sophisticated structures with complicated interactions for which either molecule might reshape itself. Even the very limited flexibility model to be considered here, using ligand conformation ensembles, requires six dimensions of exploration - three translations and three rotations - per rigid conformation. The functions for evaluating pose suitability can also be complex to calculate. Consequently, the programs being written for these biochemical simulations are extremely resource-intensive. This work introduces a pure computer science approach to the field, developing techniques to improve the effectiveness of such tools. Their architecture is generalized to an abstract pattern of nested layers for discussion, covering scoring functions, search methods, and screening overall. Based on this, new stratagems for molecular docking software design are described, including lazy or partial evaluation, geometric analysis, and parallel processing implementation. In addition, a range of novel algorithms are presented for applications such as active site detection with linear complexity (PIES) and small molecule shape description (PASTRY) for pre-alignment of ligands. The various stratagems are assessed individually and in combination, using several modified versions of an existing docking program, to demonstrate their benefit to virtual screening in practical contexts. In particular, the importance of appropriate precision in calculations is highlighted. |
| first_indexed | 2024-03-07T00:56:32Z |
| format | Thesis |
| id | oxford-uuid:8843465b-3e5f-45d9-a973-3b27949407ef |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:56:32Z |
| publishDate | 2010 |
| record_format | dspace |
| spelling | oxford-uuid:8843465b-3e5f-45d9-a973-3b27949407ef2022-03-26T22:16:02ZStratagems for effective function evaluation in computational chemistryThesishttp://purl.org/coar/resource_type/c_db06uuid:8843465b-3e5f-45d9-a973-3b27949407efComputational chemistryBioinformatics (life sciences)Computer science (mathematics)Computer aided molecular and material designComputational biochemistryApplications and algorithmsGeometryComputingHigh-Throughput ScreeningEnglishOxford University Research Archive - Valet2010Skone, GGwyn SkoneCameron, SVoiculescu, IIn recent years, the potential benefits of high-throughput virtual screening to the drug discovery community have been recognized, bringing an increase in the number of tools developed for this purpose. These programs have to process large quantities of data, searching for an optimal solution in a vast combinatorial range. This is particularly the case for protein-ligand docking, since proteins are sophisticated structures with complicated interactions for which either molecule might reshape itself. Even the very limited flexibility model to be considered here, using ligand conformation ensembles, requires six dimensions of exploration - three translations and three rotations - per rigid conformation. The functions for evaluating pose suitability can also be complex to calculate. Consequently, the programs being written for these biochemical simulations are extremely resource-intensive. This work introduces a pure computer science approach to the field, developing techniques to improve the effectiveness of such tools. Their architecture is generalized to an abstract pattern of nested layers for discussion, covering scoring functions, search methods, and screening overall. Based on this, new stratagems for molecular docking software design are described, including lazy or partial evaluation, geometric analysis, and parallel processing implementation. In addition, a range of novel algorithms are presented for applications such as active site detection with linear complexity (PIES) and small molecule shape description (PASTRY) for pre-alignment of ligands. The various stratagems are assessed individually and in combination, using several modified versions of an existing docking program, to demonstrate their benefit to virtual screening in practical contexts. In particular, the importance of appropriate precision in calculations is highlighted. |
| spellingShingle | Computational chemistry Bioinformatics (life sciences) Computer science (mathematics) Computer aided molecular and material design Computational biochemistry Applications and algorithms Geometry Computing High-Throughput Screening Skone, G Gwyn Skone Stratagems for effective function evaluation in computational chemistry |
| title | Stratagems for effective function evaluation in computational chemistry |
| title_full | Stratagems for effective function evaluation in computational chemistry |
| title_fullStr | Stratagems for effective function evaluation in computational chemistry |
| title_full_unstemmed | Stratagems for effective function evaluation in computational chemistry |
| title_short | Stratagems for effective function evaluation in computational chemistry |
| title_sort | stratagems for effective function evaluation in computational chemistry |
| topic | Computational chemistry Bioinformatics (life sciences) Computer science (mathematics) Computer aided molecular and material design Computational biochemistry Applications and algorithms Geometry Computing High-Throughput Screening |
| work_keys_str_mv | AT skoneg stratagemsforeffectivefunctionevaluationincomputationalchemistry AT gwynskone stratagemsforeffectivefunctionevaluationincomputationalchemistry |