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Hybrid Steered Molecular Dynamics-Docking: An Efficient Solution to the Problem of Ranking Inhibitor Affinities Against a Flexible Drug Target.

ABSTRACT: Existing techniques which attempt to predict the affinity of protein-ligand interactions have demonstrated a direct relationship between computational cost and prediction accuracy. We present here the first application of a hybrid ensemble docking and steered molecular dynamics scheme (with a minimized computational cost), which achieves a binding affinity rank-ordering of ligands with a Spearman correlation coefficient of 0.79 and an RMS error of 0.7 kcal/mol. The scheme, termed Flexible Enzyme Receptor Method by Steered Molecular Dynamics (FERM-SMD), is applied to an in-house collection of 17 validated ligands of glutamate racemase. The resulting improved accuracy in affinity prediction allows elucidation of the key structural components of a heretofore unreported glutamate racemase inhibitor (K(i) = 9 µM), a promising new lead in the development of antibacterial therapeutics.

SUBMITTER: Whalen KL

PROVIDER: S-EPMC3129543 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Hybrid Steered Molecular Dynamics-Docking: An Efficient Solution to the Problem of Ranking Inhibitor Affinities Against a Flexible Drug Target.

Whalen Katie L KL Chang Kevin M KM Spies M Ashley MA

Molecular informatics 20110501 5

Existing techniques which attempt to predict the affinity of protein-ligand interactions have demonstrated a direct relationship between computational cost and prediction accuracy. We present here the first application of a hybrid ensemble docking and steered molecular dynamics scheme (with a minimized computational cost), which achieves a binding affinity rank-ordering of ligands with a Spearman correlation coefficient of 0.79 and an RMS error of 0.7 kcal/mol. The scheme, termed Flexible Enzyme ...[more]

PMID: 21738559

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