A fast high-throughput logP estimation method for peptide molecules based on liquid chromatography-mass spectrometry...

We have developed a complete end-to-end high-throughput protocol for rapid estimation of logP values of peptide molecules. This scheme combines two core technologies: firstly, the "pool and split" high-throughput synthesis technology is used to efficiently prepare peptide samples; secondly, a logP detection method based on ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was developed, which relies on high-resolution mass spectrometry to accurately identify hundreds of components in mixed samples. In addition, we innovatively established a linear correlation model between chromatographic capacity factor logK' and logP, which has an excellent correlation (R² = 0.92) and can accelerate fully automated data analysis. Finally, we successfully synthesized and detected mixed samples containing 16, 81, and 256 peptide molecules, with a logP detection rate exceeding 85%. The sample processing capacity of this detection system can exceed 20000 per day, which can significantly accelerate the early screening process of lead molecules in drug development.