Conformational Selection Mechanism Provides Structural Insights into the Optimization of APC-Asef Inhibitors
| Autor: | Yuran Qiu, Yaqin Liu, Jian Zhang, Shaoyong Lu, Xinheng He, Xiao-Lan Yin, Ning Huang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
peptide drug design
Adenomatous polyposis coli Adenomatous Polyposis Coli Protein Pharmaceutical Science Peptide Computational biology Molecular Dynamics Simulation APC-Asef Ligands Article Analytical Chemistry lcsh:QD241-441 03 medical and health sciences Molecular dynamics 0302 clinical medicine lcsh:Organic chemistry Cell Movement Drug Discovery Humans Neoplasm Metastasis Physical and Theoretical Chemistry Selection (genetic algorithm) molecular dynamics (MD) simulations Cell Proliferation 030304 developmental biology chemistry.chemical_classification 0303 health sciences biology Chemistry Mechanism (biology) protein-protein interactions (PPIs) Protein dynamics Rho guanine nucleotide exchange factor 4 Organic Chemistry Binding process Chemistry (miscellaneous) 030220 oncology & carcinogenesis protein dynamics biology.protein Molecular Medicine Colorectal Neoplasms Peptides Rho Guanine Nucleotide Exchange Factors Protein Binding |
| Zdroj: | Molecules Volume 26 Issue 4 Molecules, Vol 26, Iss 962, p 962 (2021) |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules26040962 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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