Advances in analytical technologies detecting and characterizing noncovalent interactions for fragment-based drug discovery

Abstract

Detection and characterization of biomolecular interactions are the backbone of the drug discovery process. One of the most widely used approaches to developing new drugs is the fragment-based drug discovery (FBDD) strategy. The FBDD approach begins with the discovery of low molecular weight chemical fragments that bind weakly to the target of interest. The identified fragments are then combined or optimized into potent drug-like compounds. Despite its advantages over the high-throughput screening approach, its execution can be challenging. The reason is that discovering weak binders and determining how to grow or bind them are difficult. Therefore, intensive research is still underway to develop analytical technologies to detect and characterize weak, non-covalent interactions. The purpose of this article is to comprehensively review the emerging analytical technologies used in FBDD compared with the conventional ones. Particularly, we summarize their principle, advantages, limitations, and potential artifacts. For each emerging technique, we provide practical examples. Accurate detection and characterization of weak interactions are critical for the success of a FBDD project. Hence, knowledge of the features of the different techniques can support the selection and implementation of the project's analytical platform.