Energetically optimized structure-based pharmacophores
The Advantage of e-Pharmacophores
Ligand-based pharmacophore modeling and structure-based protein-ligand docking are both recognized as integral parts of drug discovery, each method offering particular strengths. Ligand-based technologies, such as 3D-pharmacophore modeling, are fast and thus useful for quickly screening large compound databases. On the other hand, structure-based approaches can yield more diverse actives and lead to important target insights, but can be time-consuming. The e-Pharmacophores method achieves the advantages of both ligand- and structure-based approaches by generating energetically optimized, structure-based pharmacophores that can be used to rapidly screen millions of compounds.
Glide XP scoring function accuracy:
The e-Pharmacophores method utilizes the Glide XP scoring function to accurately characterize protein-ligand interactions, resulting in improved database screening enrichments.
Receptor-based excluded volumes:
e-Pharmacophores allow for excluded volumes that correspond to regions of space that are occupied by the receptor.
Single and fragment modes:
Single-mode is suited to generating e-Pharmacophores from the co-crystal or docked pose of a known ligand in the target receptor. Fragment-mode will generate e-Pharmacophores from the energetically selected sites of docked fragment in cases where experimental information is unavailable. Both modes produce viable hypotheses, good database enrichments, and a diverse set of retrieved hits.
Greater levels of diversity:
e-Pharmacophores have been shown to retrieve a more diverse set of actives than traditional structure-based pharmacophore methods, making it a powerful tool for lead hopping. Speed and performance: Screen hundreds of molecules per second using either a pre-generated conformer database or generate conformers on-the-fly.
Citations and Acknowledgements
ö Salam, N.K.; Nuti, R.; Sherman, W., "Novel Method for Generating Structure-Based Pharmacophores Using Energetic Analysis," J. Chem. Inf. Model., 2009, 49, 2356–2368
ö Loving, K.; Salam, N.K.; Sherman, W., "Energetic analysis of fragment docking and application to structure-based pharmacophore hypothesis generation," J. Comput. Aided Mol. Des., 2009, 23, 541–554