Comparison of current docking tools for the simulation of inhibitor binding by the transmembrane domain of the sarco/endoplasmic reticulum calcium ATPase

Abstract

Inhibitors of the transmembrane protein sarco/endoplasmic reticulum calcium ATPase (SERCA) are invaluable tools for the study of the enzyme's physiological functions and they have been recognized as a promising new class of anticancer agents. For the discovery of novel enzyme inhibitors, small molecule docking for virtual screens of large compound libraries has become increasingly important. Since the performance of various docking routines varies considerably, depending on the target and the chemical nature of the ligand, we critically evaluated the performance of four frequently used programs - GOLD, AutoDock, Surflex-Dock, and FRED - for the docking of SERCA inhibitors based on the structures of thapsigargin, di-tert-butylhydroquinone, and cyclopiazonic acid. Evaluation criteria were docking accuracy using crystal structures as references, docking reproducibility, and correlation between docking scores and known bioactivities. The best overall results were obtained by GOLD and FRED. Docking runs with conformationally flexible binding sites produced no significant improvement of the results.

Figure 1

Location of the TG (red), BHQ (yellow), and CPA (blue) binding sites in the transmembrane domain of SERCA. The X-ray crystal structures of the TG/BHQ/SERCA (PDB entry: 2AGV [29]) and the CPA/SERCA (PDB entry: 1EAS [43]) complexes were superimposed by aligning the α-carbon atoms of the transmembrane segments.

Figure 2

Comparison of top-ranked docking poses to the known position of the inhibitors BHQ (top row), TG (middle row), and CPA (bottom row) according to crystallographic information (yellow) obtained with GOLD/ChemScore (red), AutoDock (green), Surflex-Dock (blue), and FRED/CGO (orange).

Figure 3

Correlation between docking score and bioactivity for TG and BHQ analogs. For programs with multiple scoring functions, only results for the best-performing function for these two compound classes (GOLD: ASP; FRED: CGO) are displayed.

Figure 4

Effect of flexible docking. Correlation of docking score and bioactivity for TG and BHQ analogs. Results were obtained with GOLD (GoldScore) and AutoDock using a rigid (left panels) and flexible (right panels) binding site comprised of ten residues (see Results and Discussion).

Figure 5

Docking-predicted conformational changes in the binding sited upon binding of BHQ (panels A and B) and TG (panels C and D). Docking was performed with GOLD/GoldScore (panel A for BHQ and panel C for TG) and AutoDock (panel B for BHQ and panel D for TG), showing noticeable deviations of computed side chain positions (blue) from the X-ray crystal structure (orange). Ligand positions are docking-predicted (CPK colored) and according to the crystallographic information (yellow).

Scheme 1

Molecular structure of the SERCA inhibitors TG, BHQ, and CPA.