Conformational Selection Mechanism Provides Structural Insights into the Optimization of APC-Asef Inhibitors

Abstract

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.

Understanding the P-Loop Conformation in the Determination of Inhibitor Selectivity Toward the Hepatocellular Carcinoma-Associated Dark Kinase STK17B

“…In order to unravel the predominant collective motions of different STK17B states and capture their essential degrees of freedom, we conducted principal component analysis (PCA) of STK17B in the apo, ADP-bound, and ligand-bound states. Based on the PCA, the first two principal modes of motion (i.e., principal components 1 and 2, PC1 and PC2) provide information regarding to the large-amplitude motions of different STK17B states, which represent their functional dynamics ( Masterson et al, 2011 ; Chen et al, 2019 ; Chen et al, 2021 ; He et al, 2021 ; Okeke et al, 2021 ; Rehman et al, 2021 ). In PCA, we selected all simulated trajectories for each system and subjected to RMS-fit to the same initial structure to rule out the translational and rotational motions of the protein.…”

Mechanistic Insights into the Mechanism of Inhibitor Selectivity toward the Dark Kinase STK17B against Its High Homology STK17A

“…The molecular mechanisms generalized Born surface area (MM–GBSA) binding energy calculations were performed using the following equations [ 48 , 49 , 50 , 51 , 52 ]: ∆G binding = ∆G complex − [∆G protein + ∆G ligand ] ∆G binding = ∆E gas + ∆G solvation − T∆S ∆E gas = ∆E vdW + ∆E ele ∆G solvation = ∆G GB + ∆G nonpolar ∆G nonpolar = γ × SASA + b …”

Rational Design of Peptide-Based Inhibitors Disrupting Protein-Protein Interactions

“…Peptidomimetics design is currently regarded as an eminently practical and promising approach for discovering peptide-based PPI inhibitors. So far, they have achieved fruitful success in taming series of critical but intractable PPI targets such as the MLL1-WDR5 (Karatas et al, 2013 ), APC-Asef (Jiang et al, 2017 ; He et al, 2021 ), DCN1-UBC12 (Zhou et al, 2018 ), and APP-Mint2 (Bartling et al, 2021 ). Some of them have even marched into clinical applications.…”