The quick screening of binding compounds and proteins for drug discovery and pharmacological research

Abstract

In drug discovery and pharmacological research, early identification of target molecules for compounds with pharmacological effects is crucial. However, this process often requires significant effort and can be rate-limiting, thereby slowing down research progress. This paper introduces a simplified and rapid method for quick screening of binding compounds or proteins. Utilizing Affinity Selection Mass Spectrometry (ASMS), this technique efficiently detects compound-target binding through size-exclusion chromatography and mass spectrometry. ASMS offers high sensitivity and specificity, making it ideal for accurate identification of binding interactions. We have further enhanced ASMS to handle membrane proteins without solubilization, creating Binder Selection Technology (BST). BST allows screening against both soluble and challenging membrane proteins such as GPCRs and SLC transporters. By using cell membrane fractions or organelle fractions with high target molecule expression, BST efficiently identifies potential binding compounds. This innovative method constructs a comprehensive database of binding compounds for various targets, facilitating rapid hypothesis testing and pharmacological evaluation. Additionally, BST screens 17,000 proteins, including membrane proteins, using wheat germ cell-free and animal cell expression systems. This approach allows exploration of binding interactions without labeling compounds or immobilizing proteins, preserving their native state. BST is powerful for identifying targets of compounds with known pharmacological effects but unknown targets in animal or cell-based assays. By utilizing BST, researchers can overcome bottlenecks in early drug discovery, significantly enhancing research speed and success rates. This method represents a major advancement, providing an efficient and effective way to identify and validate target molecules in drug discovery.