A Critical Assessment of the Performance of Protein−Ligand Scoring Functions Based on NMR Chemical Shift Perturbations

Abstract

We have generated docking poses for the FKBP-GPI complex using eight docking programs, and compared their scoring functions with scoring based on NMR chemical shift perturbations (NMRScore). Because the chemical shift perturbation (CSP) is exquisitely sensitive on the orientation of ligand inside the binding pocket, NMRScore offers an accurate and straightforward approach to score different poses. All scoring functions were inspected by their abilities to highly rank the native-like structures and separate them from decoy poses generated for a protein-ligand complex. The overall performance of NMRScore is much better than that of energy-based scoring functions associated with docking programs in both aspects. In summary, we find that the combination of docking programs with NMRScore results in an approach that can robustly determine the binding site structure for a protein-ligand complex, thereby, providing a new tool facilitating the structure-based drug discovery process.

The NMR2 Method to Determine Rapidly the Structure of the Binding Pocket of a Protein–Ligand Complex with High Accuracy

“…In recent decades, various methods have been developed in order to derive protein-ligand complex structures faster than with the classical NMR structure calculation protocol, but these methods mostly rely on a preliminary docking step rather than on experimentally driven calculations. Moreover, sometimes partial resonance assignments of the receptor are required [39][40][41][42][43][44][45]47,49,72]. A complex structure calculation method that is based on defined and accurate NOEs [78][79][80] but also bypasses the long and tedious protein assignment step was missing.…”

“…In cases involving weak binders, NMR spectroscopy is currently the best method to provide high resolution structural data. Recently, attempts to derive structures and/or dynamics of protein-ligand complexes by NMR more efficiently, when compared to the traditional structure calculation protocol, have been proposed including the use of ambiguous restraints [38,39] (such as ambiguous NOEs), chemical shift perturbations [40][41][42][43][44], or saturation transfer experiments [45,46] in combination with computational methods such as docking and scoring [47][48][49]. Here, we describe the advantages and disadvantages of NMR 2 over some of the most commonly used techniques to quickly determine complex structures by NMR.…”

Perspectives on NMR in drug discovery: a technique comes of age

“…Our view is that the combination of molecular docking supported by limited NMR experimental constraints (either internuclear distances information11,36 or chemical-shift mapping37,38) could represent an efficient way to rapidly gather information on ligand–target complexes without full structure determination.…”

On-the-Fly Integration of Data from a Spin-Diffusion-Based NMR Experiment into Protein–Ligand Docking

“…Protein−ligand docking methods including CSPs were published e.g. by Cioffi et al, 21 Wang et al, 22 Gonzalez-Ruiz and Gohlke, 23 and the group of Krimm. 24, 25 Even if CSPs are very sensible and, thus, provide a large amount of information, they have the disadvantage that they are not always caused by direct ligand interactions but by changes in the conformation or the dynamics of the protein upon binding and can occur far away from the actual binding site.…”