Hybrid Steered Molecular Dynamics-Docking: An Efficient Solution to the Problem of Ranking Inhibitor Affinities Against a Flexible Drug Target.
✍ Scribed by Katie L. Whalen; Kevin M. Chang; M. Ashley Spies
- Publisher
- Wiley (John Wiley & Sons)
- Year
- 2011
- Tongue
- English
- Weight
- 586 KB
- Volume
- 30
- Category
- Article
- ISSN
- 1868-1743
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✦ Synopsis
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.