A new concept for multidimensional selection of ligand conformations (MultiSelect) and multidimensional scoring (MultiScore) of protein-ligand binding affinities
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A new concept for multidimensional selection of ligand conformations (MultiSelect) and multidimensional scoring (MultiScore) of protein-ligand binding affinities. / Terp, G E; Johansen, B N; Christensen, I T; Jørgensen, Flemming Steen.
In: Journal of Medicinal Chemistry, Vol. 44, No. 14, 2001, p. 2333-43.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - A new concept for multidimensional selection of ligand conformations (MultiSelect) and multidimensional scoring (MultiScore) of protein-ligand binding affinities
AU - Terp, G E
AU - Johansen, B N
AU - Christensen, I T
AU - Jørgensen, Flemming Steen
PY - 2001
Y1 - 2001
N2 - In this work, eight different scoring functions have been combined with the aim of improving the prediction of protein-ligand binding conformations and affinities. The obtained scores were analyzed using multivariate statistical methods to generate expressions, with the ability (1) to select the best candidate between different docked conformations of an inhibitor (MultiSelect) 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 conformation of the inhibitor was selected using principal component analysis (PCA) for the scores obtained by the eight functions SCORE, LUDI, GRID, PMF_Score, D_Score, G_Score, ChemScore, and F_Score. Binding affinities were estimated based on partial least-squares projections onto latent structures (PLS) 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 experimental and calculated binding affinities. MultiSelect was evaluated by applying the same method for selecting docked conformations for 18 different protein-ligand complexes of known three-dimensional structure. In all cases, the selected ligand conformations were found to be very similar to the experimentally determined ligand conformations. A more general evaluation of MultiScore was performed using a set of 120 different protein-ligand complexes for which both the three-dimensional structures and the binding affinities were known. This approach allowed an evaluation of MultiScore independently of MultiSelect. The generality of the method was verified by obtaining R(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, respectively.
AB - In this work, eight different scoring functions have been combined with the aim of improving the prediction of protein-ligand binding conformations and affinities. The obtained scores were analyzed using multivariate statistical methods to generate expressions, with the ability (1) to select the best candidate between different docked conformations of an inhibitor (MultiSelect) 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 conformation of the inhibitor was selected using principal component analysis (PCA) for the scores obtained by the eight functions SCORE, LUDI, GRID, PMF_Score, D_Score, G_Score, ChemScore, and F_Score. Binding affinities were estimated based on partial least-squares projections onto latent structures (PLS) 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 experimental and calculated binding affinities. MultiSelect was evaluated by applying the same method for selecting docked conformations for 18 different protein-ligand complexes of known three-dimensional structure. In all cases, the selected ligand conformations were found to be very similar to the experimentally determined ligand conformations. A more general evaluation of MultiScore was performed using a set of 120 different protein-ligand complexes for which both the three-dimensional structures and the binding affinities were known. This approach allowed an evaluation of MultiScore independently of MultiSelect. The generality of the method was verified by obtaining R(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, respectively.
KW - Crystallography, X-Ray
KW - Ligands
KW - Matrix Metalloproteinases
KW - Models, Molecular
KW - Molecular Conformation
KW - Multivariate Analysis
KW - Protease Inhibitors
KW - Protein Binding
KW - Proteins
KW - Quantitative Structure-Activity Relationship
U2 - 10.1021/jm0109053
DO - 10.1021/jm0109053
M3 - Journal article
C2 - 11428927
VL - 44
SP - 2333
EP - 2343
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 14
ER -
ID: 38394265