Fragment-based metadynamics for hCES1 ligand screening
Institut for biologisk psykiatri, Roskilde, Denmark
Supervisors: H. B. Rasmussen | O. Taboureau
• Metadynamics MD is used to compute 3D free energy landscape (FEL) for the binding of ligands in the hCES1 active pocket. While computationally very efficient compared to unbiased MD, and yielding high-quality data, medium-to-large scale screening is still out of reach for this technique.
• Instead of using whole molecules, the free energy profile for synthetically/pharmaceutically-relevant fragments are computed. Reconstruction algorithm are developped to generate profile for the molecules of interest from the fragment data library. A proof of concept is developped for methylphenidate (reconstructed from phenyl, piperidine and ethyl acetate), and compared to the whole-molecule FEL.