Application of NMR and Molecular Docking in Structure-Based Drug Discovery

Abstract

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.

Probing the interaction between cHAVc3 peptide and the EC1 domain of E-cadherin using NMR and molecular dynamics simulations

“…The observed CSP could also be the result of local conformational changes in the EC1 as a consequence of peptide binding (Cui et al , 2003; Stark and Powers, 2012; Williamson et al , 1997). Although the magnitude of CSP varied from residue to residue, the residues that have CSP values higher than average are C9, Y36, I38, T63, F77, S78, I94, D103, and V112 (Figure 6C).…”

“…In this study, the binding properties of the cHAVc3 peptide to the EC1 domain of human E-cadherin were evaluated using 1 H,- 15 N-heteronuclear single quantum correlation (HSQC) NMR spectroscopy, molecular dynamics simulation, and molecular docking experiments (Stark and Powers, 2012; Williamson, 2013). The amino acid assignments in the EC1 domain were completed previously using 3D NMR spectroscopy (Prasasty et al , 2015).…”

Protein-Inhibitor Interaction Studies Using NMR

“…Finally, thanks to recent increases in computational power, in silico molecular docking is becoming widely available [121–127]. NMR titration experiments illuminate chemical-shift perturbation sites, which include, but are not limited to, the actual ligand-binding site.…”

Molecular docking of the anticancer bioactive compound proceraside with macromolecules involved in the cell cycle and DNA replication

“…However, HTS has a high failure rate, and it does not efficiently identify desired viable drug leads in most cases. Molecular docking (an alternative HTS method) provides a rapid way to evaluate likely binders from large chemical libraries with minimal costs, and it is being widely used as an important component of the drug discovery process (Stark and Powers, 2012). Recently, the cardiac glycoside proceraside A, together with frugoside and calotropin were isolated from the ethyl acetate fraction of the methanolic extract of the root bark of Calotropis procera (Aiton) W.T.…”