Prediction of ligand binding affinity using a multiple-conformations-multiple-protonation scheme: application to estrogen receptor α.

A fast method that can predict the binding affinities of chemicals to a target protein with a high degree of accuracy will be very useful in drug design and regulatory science. We have been developing a scoring function for affinity prediction, which can be applied to extensive protein systems, and also trying to generate a prediction scheme that specializes in each target protein, with as high a predictive power as possible. In this study, we have constructed a prediction scheme with target-specific scores for estimating ligand-binding affinities to human estrogen receptor α (ERα), considering the major conformational change between agonist- and antagonist-bound forms and the change in protonation states of histidine at the ligand-binding site. The generated scheme calibrated with fewer training compounds (23 for the agonist-bound form, 17 for the antagonist-bound form) demonstrated good predictive power (a predictive r(2) of 0.83 for 154 validation compounds); this was also true for compounds with frameworks that were quite different from those of the training compounds. Our prediction scheme will be useful in drug development targeting ERα and in primary screening of endocrine disruptors, and provides a successful method of affinity prediction considering the major conformational changes in a protein.

Starting point to molecular design: efficient automated 3D model builder Key3D.

Obtaining three-dimensional (3D) structures from structural formulae is a crucial process in molecular design. We have developed a new 3D model builder, Key3D, in which the simplified distance geometry technique and structure optimization based on the MMFF force field are combined. In an evaluation study using 598 crystal structures, the high performance and accuracy of Key3D were demonstrated. In the "flexible-fitting" test, which is focused on practical usefulness in the molecular design process, 88% of the Key3D structures acceptably reproduced the reference crystal structures (root-mean-square deviation <0.6 A) upon rotation of acyclic bonds. These results indicate that Key3D will be very effective in providing starting points for practical molecular design.

Effective handling of induced-fit motion in flexible docking.

For structure-based drug design, where various ligand structures need to be docked to a target protein structure, a docking method that can handle conformational flexibility of not only the ligand, but also the protein, is indispensable. We have developed a simple and effective approach for dealing with the local induced-fit motion of the target protein, and implemented it in our docking tool, ADAM. Our approach efficiently combines the following two strategies: a vdW-offset grid in which the protein cavity is enlarged uniformly, and structure optimization allowing the motion of ligand and protein atoms. To examine the effectiveness of our approach, we performed docking validation studies, including redocking in 18 test cases and foreign-docking, in which various ligands from foreign crystal structures of complexes are docked into a target protein structure, in 22 cases (on five target proteins). With the original ADAM, the correct docking modes (RMSD < 2.0 A) were not present among the top 20 models in one case of redocking and four cases of foreign-docking. When the handling of induced-fit motion was implemented, the correct solutions were acquired in all 40 test cases. In foreign-docking on thymidine kinase, the correct docking modes were obtained as the top-ranked solutions for all 10 test ligands by our combinatorial approach, and this appears to be the best result ever reported with any docking tool. The results of docking validation have thus confirmed the effectiveness of our approach, which can provide reliable docking models even in the case of foreign-docking, where conformational change of the target protein cannot be ignored. We expect that this approach will contribute substantially to actual drug design, including virtual screening.