Application of NMR and molecular docking in structure-based drug discovery

Drug discovery is a complex and costly endeavor, where few drugs that reach the clinical testing phase make it to market. High-throughput screening (HTS) is the primary method used by the pharmaceutical industry to identify initial lead compounds. Unfortunately, HTS has a high failure rate and is not particularly efficient at identifying viable drug leads. These shortcomings have encouraged the development of alternative methods to drive the drug discovery process. Specifically, nuclear magnetic resonance (NMR) spectroscopy and molecular docking are routinely being employed as important components of drug discovery research. Molecular docking provides an extremely rapid way to evaluate likely binders from a large chemical library with minimal cost. NMR ligand-affinity screens can directly detect a protein-ligand interaction, can measure a corresponding dissociation constant, and can reliably identify the ligand binding site and generate a co-structure. Furthermore, NMR ligand affinity screens and molecular docking are perfectly complementary techniques, where the combination of the two has the potential to improve the efficiency and success rate of drug discovery. This review will highlight the use of NMR ligand affinity screens and molecular docking in drug discovery and describe recent examples where the two techniques were combined to identify new and effective therapeutic drugs.