n-(4-methoxybenzyl)-n--(5-nitro-1-3-thiazol-2-yl)urea and afimoxifene

The metadynamics method has been shown to be a valuable tool to study the mechanism of molecular recognition in atomistic detail [Gervasio, F. L.; et al. J. Am. Chem. Soc. 2005, 127, 2600]. However, it requires an a priori knowledge of all slow degrees of freedom relevant to the docking/undocking mechanism. Here we investigate a combination of docking/clustering with metadynamics performed with a subset of the necessary degrees of freedom (coarse metadynamics), and show that it provides a full mechanistic insight on the protein-ligand docking mechanism. Moreover, the proposed protocol is able to clearly distinguish between crystallographic and noncrystallographic poses of protein-ligand complexes, and also to find the transition state of the full undocking mechanism, thus giving an indication on the binding free energy.

Topics: Binding Sites; Computer Simulation; Crystallography, X-Ray; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); Escherichia coli; Estrogen Receptor alpha; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Ligands; Models, Chemical; Models, Molecular; Molecular Structure; Tamoxifen; Thermodynamics; Thiazoles; Triclosan; Urea