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Mol Inform. 2011 May 16;30(5):459-471.

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

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1
Roger Adams Laboratory, Department of Biochemistry, University of Illinois, 600 S. Mathews Ave., Urbana, IL 61801, USA.

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.

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