Structural Changes Due to Antagonist Binding in Ligand Binding Pocket of Androgen Receptor Elucidated Through Molecular Dynamics Simulations
When a small molecule binds to the androgen receptor (AR), a conformational change can occur which impacts subsequent binding of co-regulator proteins and DNA. In order to accurately study this mechanism, the scientific community needs a crystal structure of the Wild type AR (WT-AR) ligand binding d...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2018-05-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/article/10.3389/fphar.2018.00492/full |
| _version_ | 1811304114100895744 |
|---|---|
| author | Sugunadevi Sakkiah Rebecca Kusko Bohu Pan Wenjing Guo Weigong Ge Weida Tong Huixiao Hong |
| author_facet | Sugunadevi Sakkiah Rebecca Kusko Bohu Pan Wenjing Guo Weigong Ge Weida Tong Huixiao Hong |
| author_sort | Sugunadevi Sakkiah |
| collection | DOAJ |
| description | When a small molecule binds to the androgen receptor (AR), a conformational change can occur which impacts subsequent binding of co-regulator proteins and DNA. In order to accurately study this mechanism, the scientific community needs a crystal structure of the Wild type AR (WT-AR) ligand binding domain, bound with antagonist. To address this open need, we leveraged molecular docking and molecular dynamics (MD) simulations to construct a structure of the WT-AR ligand binding domain bound with antagonist bicalutamide. The structure of mutant AR (Mut-AR) bound with this same antagonist informed this study. After molecular docking analysis pinpointed the suitable binding orientation of a ligand in AR, the model was further optimized through 1 μs of MD simulations. Using this approach, three molecular systems were studied: (1) WT-AR bound with agonist R1881, (2) WT-AR bound with antagonist bicalutamide, and (3) Mut-AR bound with bicalutamide. Our structures were very similar to the experimentally determined structures of both WT-AR with R1881 and Mut-AR with bicalutamide, demonstrating the trustworthiness of this approach. In our model, when WT-AR is bound with bicalutamide, Val716/Lys720/Gln733, or Met734/Gln738/Glu897 move and thus disturb the positive and negative charge clumps of the AF2 site. This disruption of the AF2 site is key for understanding the impact of antagonist binding on subsequent co-regulator binding. In conclusion, the antagonist induced structural changes in WT-AR detailed in this study will enable further AR research and will facilitate AR targeting drug discovery. |
| first_indexed | 2024-04-13T08:00:07Z |
| format | Article |
| id | doaj.art-8205112e8e1c41a4baf1f4722ddcc68c |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T08:00:07Z |
| publishDate | 2018-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-8205112e8e1c41a4baf1f4722ddcc68c2022-12-22T02:55:17ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-05-01910.3389/fphar.2018.00492329304Structural Changes Due to Antagonist Binding in Ligand Binding Pocket of Androgen Receptor Elucidated Through Molecular Dynamics SimulationsSugunadevi Sakkiah0Rebecca Kusko1Bohu Pan2Wenjing Guo3Weigong Ge4Weida Tong5Huixiao Hong6Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, United StatesImmuneering Corporation, Cambridge, MA, United StatesDivision of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, United StatesDivision of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, United StatesDivision of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, United StatesDivision of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, United StatesDivision of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, United StatesWhen a small molecule binds to the androgen receptor (AR), a conformational change can occur which impacts subsequent binding of co-regulator proteins and DNA. In order to accurately study this mechanism, the scientific community needs a crystal structure of the Wild type AR (WT-AR) ligand binding domain, bound with antagonist. To address this open need, we leveraged molecular docking and molecular dynamics (MD) simulations to construct a structure of the WT-AR ligand binding domain bound with antagonist bicalutamide. The structure of mutant AR (Mut-AR) bound with this same antagonist informed this study. After molecular docking analysis pinpointed the suitable binding orientation of a ligand in AR, the model was further optimized through 1 μs of MD simulations. Using this approach, three molecular systems were studied: (1) WT-AR bound with agonist R1881, (2) WT-AR bound with antagonist bicalutamide, and (3) Mut-AR bound with bicalutamide. Our structures were very similar to the experimentally determined structures of both WT-AR with R1881 and Mut-AR with bicalutamide, demonstrating the trustworthiness of this approach. In our model, when WT-AR is bound with bicalutamide, Val716/Lys720/Gln733, or Met734/Gln738/Glu897 move and thus disturb the positive and negative charge clumps of the AF2 site. This disruption of the AF2 site is key for understanding the impact of antagonist binding on subsequent co-regulator binding. In conclusion, the antagonist induced structural changes in WT-AR detailed in this study will enable further AR research and will facilitate AR targeting drug discovery.http://journal.frontiersin.org/article/10.3389/fphar.2018.00492/fullandrogen receptormolecular dynamics simulationsinduced molecular dockingbicalutamideagonistantagonist |
| spellingShingle | Sugunadevi Sakkiah Rebecca Kusko Bohu Pan Wenjing Guo Weigong Ge Weida Tong Huixiao Hong Structural Changes Due to Antagonist Binding in Ligand Binding Pocket of Androgen Receptor Elucidated Through Molecular Dynamics Simulations Frontiers in Pharmacology androgen receptor molecular dynamics simulations induced molecular docking bicalutamide agonist antagonist |
| title | Structural Changes Due to Antagonist Binding in Ligand Binding Pocket of Androgen Receptor Elucidated Through Molecular Dynamics Simulations |
| title_full | Structural Changes Due to Antagonist Binding in Ligand Binding Pocket of Androgen Receptor Elucidated Through Molecular Dynamics Simulations |
| title_fullStr | Structural Changes Due to Antagonist Binding in Ligand Binding Pocket of Androgen Receptor Elucidated Through Molecular Dynamics Simulations |
| title_full_unstemmed | Structural Changes Due to Antagonist Binding in Ligand Binding Pocket of Androgen Receptor Elucidated Through Molecular Dynamics Simulations |
| title_short | Structural Changes Due to Antagonist Binding in Ligand Binding Pocket of Androgen Receptor Elucidated Through Molecular Dynamics Simulations |
| title_sort | structural changes due to antagonist binding in ligand binding pocket of androgen receptor elucidated through molecular dynamics simulations |
| topic | androgen receptor molecular dynamics simulations induced molecular docking bicalutamide agonist antagonist |
| url | http://journal.frontiersin.org/article/10.3389/fphar.2018.00492/full |
| work_keys_str_mv | AT sugunadevisakkiah structuralchangesduetoantagonistbindinginligandbindingpocketofandrogenreceptorelucidatedthroughmoleculardynamicssimulations AT rebeccakusko structuralchangesduetoantagonistbindinginligandbindingpocketofandrogenreceptorelucidatedthroughmoleculardynamicssimulations AT bohupan structuralchangesduetoantagonistbindinginligandbindingpocketofandrogenreceptorelucidatedthroughmoleculardynamicssimulations AT wenjingguo structuralchangesduetoantagonistbindinginligandbindingpocketofandrogenreceptorelucidatedthroughmoleculardynamicssimulations AT weigongge structuralchangesduetoantagonistbindinginligandbindingpocketofandrogenreceptorelucidatedthroughmoleculardynamicssimulations AT weidatong structuralchangesduetoantagonistbindinginligandbindingpocketofandrogenreceptorelucidatedthroughmoleculardynamicssimulations AT huixiaohong structuralchangesduetoantagonistbindinginligandbindingpocketofandrogenreceptorelucidatedthroughmoleculardynamicssimulations |