Reduction of false positives in structure-based virtual screening when receptor plasticity is considered
Structure-based virtual screening for selecting potential drug candidates is usually challenged by how numerous false positives in a molecule library are excluded when receptor plasticity is considered. In this study, based on the binding energy landscape theory, a hypothesis that a true inhibitor c...
| Main Authors: | , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2015
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| Online Access: | https://hdl.handle.net/10356/105702 http://hdl.handle.net/10220/25987 |
| _version_ | 1826122879976079360 |
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| author | Awuni, Yaw Mu, Yuguang |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Awuni, Yaw Mu, Yuguang |
| author_sort | Awuni, Yaw |
| collection | NTU |
| description | Structure-based virtual screening for selecting potential drug candidates is usually challenged by how numerous false positives in a molecule library are excluded when receptor plasticity is considered. In this study, based on the binding energy landscape theory, a hypothesis that a true inhibitor can bind to different conformations of the binding site favorably was put forth, and related strategies to defeat this challenge were devised; reducing false positives when receptor plasticity is considered. The receptor in the study is the influenza A nucleoprotein, whose oligomerization is a requirement for RNA binding. The structural flexibility of influenza A nucleoprotein was explored by molecular dynamics simulations. The resultant distinctive structures and the crystal structure were used as receptor models in docking exercises in which two binding sites, the tail-loop binding pocket and the RNA binding site, were targeted with the Otava PrimScreen1 diversity-molecule library using the GOLD software. The intersection ligands that were listed in the top-ranked molecules from all receptor models were selected. Such selection strategy successfully distinguished high-affinity and low-affinity control molecules added to the molecule library. This work provides an applicable approach for reducing false positives and selecting true ligands from molecule libraries. |
| first_indexed | 2024-10-01T05:55:27Z |
| format | Journal Article |
| id | ntu-10356/105702 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:55:27Z |
| publishDate | 2015 |
| record_format | dspace |
| spelling | ntu-10356/1057022023-02-28T17:05:49Z Reduction of false positives in structure-based virtual screening when receptor plasticity is considered Awuni, Yaw Mu, Yuguang School of Biological Sciences DRNTU::Science::Biological sciences::Molecular biology Structure-based virtual screening for selecting potential drug candidates is usually challenged by how numerous false positives in a molecule library are excluded when receptor plasticity is considered. In this study, based on the binding energy landscape theory, a hypothesis that a true inhibitor can bind to different conformations of the binding site favorably was put forth, and related strategies to defeat this challenge were devised; reducing false positives when receptor plasticity is considered. The receptor in the study is the influenza A nucleoprotein, whose oligomerization is a requirement for RNA binding. The structural flexibility of influenza A nucleoprotein was explored by molecular dynamics simulations. The resultant distinctive structures and the crystal structure were used as receptor models in docking exercises in which two binding sites, the tail-loop binding pocket and the RNA binding site, were targeted with the Otava PrimScreen1 diversity-molecule library using the GOLD software. The intersection ligands that were listed in the top-ranked molecules from all receptor models were selected. Such selection strategy successfully distinguished high-affinity and low-affinity control molecules added to the molecule library. This work provides an applicable approach for reducing false positives and selecting true ligands from molecule libraries. Published version 2015-06-22T06:37:03Z 2019-12-06T21:56:08Z 2015-06-22T06:37:03Z 2019-12-06T21:56:08Z 2015 2015 Journal Article Awuni, Y., & Mu, Y. (2015). Reduction of false positives in structure-based virtual screening when receptor plasticity is considered. Molecules, 20(3), 5152-5164. 1420-3049 https://hdl.handle.net/10356/105702 http://hdl.handle.net/10220/25987 10.3390/molecules20035152 en Molecules © 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/). application/pdf |
| spellingShingle | DRNTU::Science::Biological sciences::Molecular biology Awuni, Yaw Mu, Yuguang Reduction of false positives in structure-based virtual screening when receptor plasticity is considered |
| title | Reduction of false positives in structure-based virtual screening when receptor plasticity is considered |
| title_full | Reduction of false positives in structure-based virtual screening when receptor plasticity is considered |
| title_fullStr | Reduction of false positives in structure-based virtual screening when receptor plasticity is considered |
| title_full_unstemmed | Reduction of false positives in structure-based virtual screening when receptor plasticity is considered |
| title_short | Reduction of false positives in structure-based virtual screening when receptor plasticity is considered |
| title_sort | reduction of false positives in structure based virtual screening when receptor plasticity is considered |
| topic | DRNTU::Science::Biological sciences::Molecular biology |
| url | https://hdl.handle.net/10356/105702 http://hdl.handle.net/10220/25987 |
| work_keys_str_mv | AT awuniyaw reductionoffalsepositivesinstructurebasedvirtualscreeningwhenreceptorplasticityisconsidered AT muyuguang reductionoffalsepositivesinstructurebasedvirtualscreeningwhenreceptorplasticityisconsidered |