Conformational Selection Mechanism Provides Structural Insights into the Optimization of APC-Asef Inhibitors
Metastasis is the major cause of death in colorectal cancer and it has been proven that inhibiting an interaction between adenomatous polyposis coli (APC) and Rho guanine nucleotide exchange factor 4 (Asef) efficaciously restrain metastasis. However, current inhibitors cannot achieve a satisfying ef...
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| Format: | Article |
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MDPI AG
2021-02-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/4/962 |
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| author | Xinheng He Ning Huang Yuran Qiu Jian Zhang Yaqin Liu Xiao-Lan Yin Shaoyong Lu |
| author_facet | Xinheng He Ning Huang Yuran Qiu Jian Zhang Yaqin Liu Xiao-Lan Yin Shaoyong Lu |
| author_sort | Xinheng He |
| collection | DOAJ |
| description | Metastasis is the major cause of death in colorectal cancer and it has been proven that inhibiting an interaction between adenomatous polyposis coli (APC) and Rho guanine nucleotide exchange factor 4 (Asef) efficaciously restrain metastasis. However, current inhibitors cannot achieve a satisfying effect in vivo and need to be optimized. In the present study, we applied molecular dynamics (MD) simulations and extensive analyses to apo and holo APC systems in order to reveal the inhibitor mechanism in detail and provide insights into optimization. MD simulations suggested that apo APC takes on a broad array of conformations and inhibitors stabilize conformation selectively. Representative structures in trajectories show specific APC-ligand interactions, explaining the different binding process. The stability and dynamic properties of systems elucidate the inherent factors of the conformation selection mechanism. Binding free energy analysis quantitatively confirms key interface residues and guide optimization. This study elucidates the conformation selection mechanism in APC-Asef inhibition and provides insights into peptide-based drug design. |
| first_indexed | 2024-03-09T00:58:12Z |
| format | Article |
| id | doaj.art-fbd845a3ea8c4cbcb678a759dd82fae1 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T00:58:12Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-fbd845a3ea8c4cbcb678a759dd82fae12023-12-11T16:47:48ZengMDPI AGMolecules1420-30492021-02-0126496210.3390/molecules26040962Conformational Selection Mechanism Provides Structural Insights into the Optimization of APC-Asef InhibitorsXinheng He0Ning Huang1Yuran Qiu2Jian Zhang3Yaqin Liu4Xiao-Lan Yin5Shaoyong Lu6Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, ChinaNorthern Huashan Hospital, Fudan University, Shanghai 201907, ChinaKey Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, ChinaKey Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, ChinaMedicinal Chemistry and Bioinformatics Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, ChinaDepartment of Radiotherapy, Changhai Hospital (Hongkou District) Affiliated to Naval Medical University, Shanghai 200081, ChinaKey Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, ChinaMetastasis is the major cause of death in colorectal cancer and it has been proven that inhibiting an interaction between adenomatous polyposis coli (APC) and Rho guanine nucleotide exchange factor 4 (Asef) efficaciously restrain metastasis. However, current inhibitors cannot achieve a satisfying effect in vivo and need to be optimized. In the present study, we applied molecular dynamics (MD) simulations and extensive analyses to apo and holo APC systems in order to reveal the inhibitor mechanism in detail and provide insights into optimization. MD simulations suggested that apo APC takes on a broad array of conformations and inhibitors stabilize conformation selectively. Representative structures in trajectories show specific APC-ligand interactions, explaining the different binding process. The stability and dynamic properties of systems elucidate the inherent factors of the conformation selection mechanism. Binding free energy analysis quantitatively confirms key interface residues and guide optimization. This study elucidates the conformation selection mechanism in APC-Asef inhibition and provides insights into peptide-based drug design.https://www.mdpi.com/1420-3049/26/4/962APC-Asefprotein-protein interactions (PPIs)molecular dynamics (MD) simulationsprotein dynamicspeptide drug design |
| spellingShingle | Xinheng He Ning Huang Yuran Qiu Jian Zhang Yaqin Liu Xiao-Lan Yin Shaoyong Lu Conformational Selection Mechanism Provides Structural Insights into the Optimization of APC-Asef Inhibitors Molecules APC-Asef protein-protein interactions (PPIs) molecular dynamics (MD) simulations protein dynamics peptide drug design |
| title | Conformational Selection Mechanism Provides Structural Insights into the Optimization of APC-Asef Inhibitors |
| title_full | Conformational Selection Mechanism Provides Structural Insights into the Optimization of APC-Asef Inhibitors |
| title_fullStr | Conformational Selection Mechanism Provides Structural Insights into the Optimization of APC-Asef Inhibitors |
| title_full_unstemmed | Conformational Selection Mechanism Provides Structural Insights into the Optimization of APC-Asef Inhibitors |
| title_short | Conformational Selection Mechanism Provides Structural Insights into the Optimization of APC-Asef Inhibitors |
| title_sort | conformational selection mechanism provides structural insights into the optimization of apc asef inhibitors |
| topic | APC-Asef protein-protein interactions (PPIs) molecular dynamics (MD) simulations protein dynamics peptide drug design |
| url | https://www.mdpi.com/1420-3049/26/4/962 |
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