Prediction of Ion Channel Allosteric Sites

Ion channels are important medical targets. Creative Bioarray is committed to developing a variety of computational methods to help clients predict the binding sites and allosteric sites of ion channels, providing important information for the discovery of high-efficiency ion channel modulators and the development of drugs for the treatment of ion channel diseases.

Introduction

Currently, most small-molecule drugs on the market target proteins including ion channels. These drugs have high affinity and high specificity for the active site of the protein, and achieve modulation of protein activity by directly binding to the site. Therefore, the development of multiple computational methods to identify potential binding sites of ion channels is critical for the development of drugs.

In addition to the binding site, there are one or several sites on the ion channel that can bind to specific molecules non-covalently. These binding events may lead to conformational changes of channel proteins and ultimately to the controlled up- and down-regulation of ion channel activity. This allosteric modulation has significant advantages in drug development over orthosteric site binding. Therefore, identifying allosteric sites of ion channels is of great significance for the development of novel targeted drugs. With the progress of protein crystal analysis and AI-assisted allosteric site prediction methods in recent years, there is hope for the large-scale geographical design of allosteric drugs.

Fig. 1 Schematic representation of the various orthosteric and allosteric sites in pLGICs. (Changeux, 2013)

Prediction of the Potential Binding Sites

We have developed a variety of methods to provide binding site prediction services for our clients, including:

• Structure-based approach.
• A method for inferring binding sites from template proteins with similar structures. This method allows predicting the binding sites of channel proteins with high structural similarity templates based on the rapid accumulation of protein structures.
• Artificial intelligence method. This method uses schemes such as 3D convolutional neural networks to predict the structure or interaction mode of binding sites.

In addition, we also provide clients with the calculation service of the binding affinity of each site.

Prediction of the Potential Allosteric Sites

• We provide clients with prediction services of potential allosteric sites by combining machine learning methods and molecular simulation strategies.
• Prediction based on single channel protein structure. This method allows predicting allosteric sites by analyzing the correlation between orthogonal sites and allosteric sites based on the perturbation applied to orthogonal sites using a network model.
• Prediction by combining with trajectories from molecular simulation. We improved the sampling efficiency through reinforced dynamics scheme to improve the efficiency of the simulation-based method.
• We help clients predict the allosteric communication in channel proteins by the evolutionary-based approach.

Creative Bioarray has a first-class and comprehensive technology platform and has accumulated a lot of experience in ion channel bioinformatics analysis. We have the strength to provide clients with prediction services of ion channel binding sites and allosteric sites. If you are interested in our services, please feel free to contact us for more details.

Reference

1. Changeux, J. P. The concept of allosteric interaction and its consequences for the chemistry of the brain. Journal of Biological Chemistry, 2013, 288(38): 26969-26986.