Calculating an optimal box size for ligand docking and virtual screening against experimental and predicted binding pockets

Abstract

BackgroundComputational approaches have emerged as an instrumental methodology in modern research. For example, virtual screening by molecular docking is routinely used in computer-aided drug discovery. One of the critical parameters for ligand docking is the size of a search space used to identify low-energy binding poses of drug candidates. Currently available docking packages often come with a default protocol for calculating the box size, however, many of these procedures have not been systematically evaluated.MethodsIn this study, we investigate how the docking accuracy of AutoDock Vina is affected by the selection of a search space. We propose a new procedure for calculating the optimal docking box size that maximizes the accuracy of binding pose prediction against a non-redundant and representative dataset of 3,659 protein-ligand complexes selected from the Protein Data Bank. Subsequently, we use the Directory of Useful Decoys, Enhanced to demonstrate that the optimized docking box size also yields an improved ranking in virtual screening. Binding pockets in both datasets are derived from the experimental complex structures and, additionally, predicted by eFindSite.ResultsA systematic analysis of ligand binding poses generated by AutoDock Vina shows that the highest accuracy is achieved when the dimensions of the search space are 2.9 times larger than the radius of gyration of a docking compound. Subsequent virtual screening benchmarks demonstrate that this optimized docking box size also improves compound ranking. For instance, using predicted ligand binding sites, the average enrichment factor calculated for the top 1 % (10 %) of the screening library is 8.20 (3.28) for the optimized protocol, compared to 7.67 (3.19) for the default procedure. Depending on the evaluation metric, the optimal docking box size gives better ranking in virtual screening for about two-thirds of target proteins.ConclusionsThis fully automated procedure can be used to optimize docking protocols in order to improve the ranking accuracy in production virtual screening simulations. Importantly, the optimized search space systematically yields better results than the default method not only for experimental pockets, but also for those predicted from protein structures. A script for calculating the optimal docking box size is freely available at www.brylinski.org/content/docking-box-size.Graphical AbstractWe developed a procedure to optimize the box size in molecular docking calculations. Left panel shows the predicted binding pose of NADP (green sticks) compared to the experimental complex structure of human aldose reductase (blue sticks) using a default protocol. Right panel shows the docking accuracy using an optimized box size.

Assessing the similarity of ligand binding conformations with the Contact Mode Score

“…Subsequently, each randomized ligand was re-docked to the protein with AutoDock Vina (Trott and Olson, 2010). The docking box was set to an optimal size based on the radius of gyration of the ligand (Feinstein and Brylinski, 2015) and the binding pocket center was set to the geometric center of the compound bound in the experimental complex. This procedure produced 2 200 docked conformations of query ligands.…”

Acoplamiento Molecular: Avances Recientes y Retos

“…Therefore, the results are dependent of the GRID resolution and size. Recently, Feinstein & Brylinski (2015) studied the influence of box size on the identification of hits and virtual screening time, as this may be done on the fly or recalculated for each ligand. A good example to illustrate this point are Autodock and Vina: the former needs the precalculation of GRID for molecular docking while the latter does it on the fly yielding a faster calculation (Trott & Olson, 2009).…”

In Silico Docking Studies on Kaempferitrin With Diverse Inflammatory and Apoptotic Proteins Functional Approach Towards the Colon Cancer

“…RMSD was used for the assessment of docking accuracy of the fraction of protein-ligand contacts [40] and the successful prediction of RMSD<1Å [41]. The RMSD prediction was evaluated from the lower and upper binding energies of proteins with kaempferitrin.…”