A novel method using nuclear magnetic resonance for plasma protein binding assessment in drug discovery programs

Abstract

A new methodology based on Nuclear Magnetic Resonance (NMR) was developed to determine plasma protein binding (PPB) of drug candidates in drug discovery programs. A strong correlation was found between the attenuation of NMR signals of diverse drugs in the presence of different plasma concentrations and their fraction bound (f_b) reported in the literature. Based on these results, a protocol for a rapid calculation of f_b of small molecules was established. The advantage of using plasma instead of purified recombinant proteins and the possibility of pool analysis to increase throughput were also evaluated. This novel methodology proved to be very versatile, cost-effective, fast and suitable for automation. As a plus, it contemporarily provides a quality check and solubility of the compound.

Keywords: Drug discovery; NMR; Plasma protein binding; Protein-ligand interaction; Screening.