Structural Characterization and Computer-Aided Optimization of a Small-Molecule Inhibitor of the Arp2/3 Complex, a Key Regulator of the Actin Cytoskeleton
| Autor: | Adam C. Glass, Shih-Yuan Liu, Zoe Cournia, Min Suk Han, Brad J. Nolen, George Patargias, Andrew W. Baggett |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Regulator Arp2/3 complex macromolecular substances Biochemistry Actin-Related Protein 2-3 Complex Article Small Molecule Libraries Structure-Activity Relationship Drug Discovery Animals Structure–activity relationship General Pharmacology Toxicology and Pharmaceutics Actin Pharmacology Dose-Response Relationship Drug Molecular Structure biology Organic Chemistry Stereoisomerism Actin cytoskeleton Small molecule Cell biology Actin Cytoskeleton Docking (molecular) biology.protein Computer-Aided Design Molecular Medicine Cattle |
| Zdroj: | ChemMedChem. 7:1286-1294 |
| ISSN: | 1860-7179 |
| DOI: | 10.1002/cmdc.201200104 |
| Popis: | CK-666 (1) is a recently discovered small-molecule inhibitor of the actin-related protein 2/3 (Arp2/3) complex, a key actin cytoskeleton regulator with roles in bacterial pathogenesis and cancer cell motility. Although 1 is commercially available, the crystal structure of Arp2/3 complex with 1 bound has not been reported, making its mechanism of action uncertain. Furthermore, its relatively low potency increases its potential for off-target effects in vivo, complicating interpretation of its influence in cell biological studies and precluding its clinical use. Herein we report the crystal structure of 1 bound to Arp2/3 complex, which reveals that 1 binds between the Arp2 and Arp3 subunits to stabilize the inactive conformation of the complex. Based on the crystal structure, we used computational docking and free-energy perturbation calculations of monosubstituted derivatives of 1 to guide optimization efforts. Biochemical assays of ten newly synthesized compounds led to the identification of compound 2, which exhibits a threefold increase in inhibitory activity in vitro relative to 1. In addition, our computational analyses unveiled a surface groove at the interface of the Arp2 and Arp3 subunits that can be exploited for additional structure-based optimization. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text