0000000000469547
AUTHOR
Almerico Anna Maria
The Molecular dYnamics SHAred PharmacophorE (MYSHAPE) approacha new tool to arise docking and pharmacophore modeling performance: virtues and vices
In a recent paper, we presented a new virtual screening workflow that addresses the arising issues of molecular docking and pharmacophore modeling when using a single set of coordinates and a single active ligand [1]. MD simulations were carried out and ligand-protein interactions were analyzed and collected together with their appearance frequency. A pharmacophore model was then created using only the common feature patterns that all the ligands exhibited during MD simulations. This ‘Molecular dYnamics SHAred PharmacophorE’ was then used for virtual screening on active and inactive molecules library. MYSHAPE was also used as constraints for the creation of the docking grid. The application…
Exploring the non-covalent ligand-binding mechanism on immunoproteasome by enhanced Molecular Dynamics
Selective inhibition of immunoproteasome is a valuable strategy to treat autoimmune and inflammatory diseases, and hematologic malignancies. In particular, non-covalent inhibition is strongly desirable because it is free of the drawbacks and side effects associated with covalent inhibition. Recently, a new series of amide derivatives with Ki values in the low/submicromolar ranges toward the β1i subunit have been identified as non-covalent inhibitors 1 . We investigated the binding mechanism of the most potent and selective inhibitor (1) to elucidate the steps from the ligand entrance into the binding pocket to the ligand-induced conformational changes. We carried out a total of 400ns of MD-…