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Can I create a pharmacophore hypothesis based only on my protein binding site, without having a native ligand?

You can do this with the script E-Pharmacophores (formerly Score Phase Hypothesis by XPDes). This script is available from the Script Center, and is included in the software distribution as of Suite 2011 (Scripts → Docking Post-processing → E-Pharmacophores).

You will need some structures in the binding site on which to base the pharmacophore model. For this purpose, we recommend that you dock fragment molecules to your binding site with Glide XP and ensure that you select "Write XP descriptor information." For example, you could use the fragment molecules provided on our website: https://www.schrodinger.com/productpage/14/5/73/

The E-Pharmacophores script creates a Phase hypothesis from docked poses based on the Glide XP descriptor energies associated with each pharmacophore feature. The pose viewer file from Glide is required as input. This file contains the XP descriptors in Suite 2011; in earlier releases, an XP descriptor (*.xpdes) file is required as well. Because you will likely have many docked fragment poses from Glide, you should use the default option to cluster the fragments by volume overlap. Receptor-based excluded volumes can be optionally included.

The method is described in these two papers:

J. Chem. Inf. Model., 2009, 49 (10), 2356-2368 http://pubs.acs.org/doi/abs/10.1021/ci900212v
J. Comp. Aided Mol Des., 2009, 23 (8), 541-554 http://www.springerlink.com/content/07747281v175403g/

Keywords: receptor-based pharmacophore, e-pharmacophore

Related Articles:

#131: Is it possible to generate a structure-based pharmacophore model from the receptor binding site?

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