Validation of Molecular Docking Calculations Involving FGF-1 and FGF-2

Abstract

A predictive relationship between calculated and observed binding affinities for the complexation of ligands to the fibroblast growth factors FGF-1 and FGF-2 based on molecular docking calculations is described. The majority of the ligands examined in this study have high conformational flexibility, and to account for this, multiple conformers were generated for each and subsequently used in flexible docking calculations. Two scoring functions, Gscore and Emodel, were used to quantify the protein:ligand interaction of which the Emodel score showed the best correlation with experimental binding energies. Both scoring functions, however, predicted similar locations for the ligand sulfate groups in the binding site. The van der Waals radii of nonpolar atoms of both the protein and ligand, which modify the effective sizes of both the protein binding site and the ligand, were also systematically altered by factors of 1.0, 0.9, and 0.8 in order to optimize the conditions for predictive docking. Least squares analyses of the Emodel scores against experimental binding energies yielded best r(2) values of 0.91 and 0.83 for FGF-1 and FGF-2, respectively, with slightly lower q(2) values. Optimized scale factor combinations in conjunction with the least squares lines of best fit based on the Emodel function were used to define a predictive model that was tested against ligands not included in the original set. Acceptable predictions of binding affinity were obtained for use in the initial screening of potential leadlike molecules for both FGF-1 and FGF-2.

Can we use docking and scoring for hit-to-lead optimization?

“…Bytheway and Cochran [26] noted that Emodel correlated better with binding affinity than GlideScore. Thus we tested the efficiency of Emodel on all our docking runs.…”

“…This is understandable since a difference of 1.36 kcal/mol in binding free energy leads to a 10-fold difference in Ki. However, there are reports about good correlation between docking score and experimental binding energies [26].…”

“…Previously published studies [26,27] have used a very small number of compounds. Small datasets do not contain the diversity and information necessary to characterize computational methods.…”

A surface plasmon resonance-based solution affinity assay for heparan sulfate-binding proteins

“…The assay was used to measure the binding of various ligands, including the antiangiogenic drug candidate PI-88 as well as heparin and HS, to the heparinbinding, angiogenic growth factors FGF-1, FGF-2 and VEGF [23]. The assay was subsequently applied to the screening of various heparin-mimetic compounds as potential antiangiogenic, anti-cancer agents [12,[24][25][26][27][28].…”

Molecular docking/dynamics studies of Aurora A kinase inhibitors

“…Although details on the methodology used by Glide are described elsewhere [20][21][22][23], a short description is provided below. The binding site, for which the various energy grids were calculated and stored, is defined in terms of two concentric cubes: the bounding box, which must contain the center of any acceptable ligand pose, and the enclosing box, which must contain all ligand atoms of an acceptable pose.…”