A new concept for multidimensional selection of ligand conformations (MultiSelect) and multidimensional scoring (MultiScore) of protein-ligand binding affinities
Ge. Terp et al., A new concept for multidimensional selection of ligand conformations (MultiSelect) and multidimensional scoring (MultiScore) of protein-ligand binding affinities, J MED CHEM, 44(14), 2001, pp. 2333-2343
In this work, eight different scoring functions have been combined with the
aim of improving I the prediction of protein-ligand binding conformations
and affinities. The obtained scores were analyzed using multivariate statis
tical methods to generate expressions,,with the ability (1) to select the b
est candidate between different docked conformations of an inhibitor (Multi
Select) and (2) to quantify the protein-ligand binding affinity (MultiScore
). By use of the docking program GOLD, 40 different inhibitors were docked
into the active site of three matrix metalloproteinases (MMP's), yielding a
total of 120 enzyme-inhibitor complexes. For each complex, a single confor
mation of the inhibitor was selected using principal component analysis (PC
A) for the scores obtained by the eight functions SCORE, LUDI, GRID, PMF_Sc
ore, D_Score, G_Score, ChemScore, and F_Score. Binding affinities were esti
mated based on partial least-squares projections onto latent structures (PL
S) on the eight scores of each selected: inhibitor conformation. By use of
this procedure, R-2 = 0.78 and Q(2) = 0.78 were obtained when comparing exp
erimental and calculated binding affinities. MultiSelect was evaluated by a
pplying the same method for selecting docked conformations for 18 different
protein-ligand;complexes of known three-dimensional structure. In all case
s, the selected ligand conformations were found to be very similar to the e
xperimentally determined ligand conformations. A more general evaluation of
MultiScore was performed using a set of 120 different protein-ligand compl
exes for which both the three-dimensional structures and the binding affini
ties were known. This approach: allowed an evaluation of MultiScore indepen
dently of MultiSelect. The generality of the method was verified by obtaini
ng Q(2) = 0.68 and Q(2) = 0.67, when comparing calculated and experimental
binding affinities for the 120 X-ray structures. In all cases, LUDI, SCORE,
GRID, and F_Score were included as important functions, whereas the fifth
function was PMF_Score and ChemScore for the MMP and X-ray models, respecti
vely.