Large scale free energy calculations for blind predictions of protein-ligand binding: the D3R Grand Challenge 2015

Abstract

We describe binding free energy calculations in the D3R Grand Challenge 2015 for blind prediction of the binding affinities of 180 ligands to Hsp90. The present D3R challenge was built around experimental datasets involving Heat shock protein (Hsp) 90, an ATP-dependent molecular chaperone which is an important anticancer drug target. The Hsp90 ATP binding site is known to be a challenging target for accurate calculations of ligand binding affinities because of the ligand-dependent conformational changes in the binding site, the presence of ordered waters and the broad chemical diversity of ligands that can bind at this site. Our primary focus here is to distinguish binders from nonbinders. Large scale absolute binding free energy calculations that cover over 3000 protein-ligand complexes were performed using the BEDAM method starting from docked structures generated by Glide docking. Although the ligand dataset in this study resembles an intermediate to late stage lead optimization project while the BEDAM method is mainly developed for early stage virtual screening of hit molecules, the BEDAM binding free energy scoring has resulted in a moderate enrichment of ligand screening against this challenging drug target. Results show that, using a statistical mechanics based free energy method like BEDAM starting from docked poses offers better enrichment than classical docking scoring functions and rescoring methods like Prime MM-GBSA for the Hsp90 data set in this blind challenge. Importantly, among the three methods tested here, only the mean value of the BEDAM binding free energy scores is able to separate the large group of binders from the small group of nonbinders with a gap of 2.4 kcal/mol. None of the three methods that we have tested provided accurate ranking of the affinities of the 147 active compounds. We discuss the possible sources of errors in the binding free energy calculations. The study suggests that BEDAM can be used strategically to discriminate binders from nonbinders in virtual screening and to more accurately predict the ligand binding modes prior to the more computationally expensive FEP calculations of binding affinity.

Keywords: Binding free energy; D3R; Docking; GC2015; Hsp90; ROC.

Fig. 1

Hsp90 ATP binding site and representative ligands with different chemical scaffolds. a Benzofuran; b anthraquinone; c benzoimidazolone with resorcinol substitution; d aminopurine derivative

Fig. 2

ROC curves obtained with BEDAM, glide SP and prime MM-GB/SA

Fig. 3

The distribution of AUC among 83 submissions in the D3R GC2015 challenge. The BEDAM result is colored red

Fig. 4

The distribution of binding score values from BEDAM, Glide SP and MM-GB/SA for the 180 Hsp90 ligands

Fig. 5

ROC curves for BEDAM binding free energy scoring and binding energy scoring

Fig. 6

Representative phenol compounds

Fig. 7

The final frame of the complex of Hsp90 and ligand 73 in the λ = 1 DDM trajectory. The carbon atoms of the ligand are shown in yellow. The intermolecular hydrogen bonds are shown as green dashed lines

Fig. 8

Importance of initial docked structure to binding free energy calculation

Fig. 9

The experimental and calculated ΔG for the ligands containing benzophenone scaffold