The role of virtual ligand screening in modern drug discovery is to mine large chemical collections and to prioritize for experimental testing a comparatively small and diverse set of compounds with expected activity against a target. Several studies have pointed out that the performance of virtual ligand screening can be improved by taking into account receptor flexibility. Here, we systematically assess how multiple crystallographic receptor conformations, a powerful way of discretely representing protein plasticity, can be exploited in screening protocols to separate binders from non-binders. Our analyses encompass 36 targets of pharmaceutical relevance and are based on actual molecules with reported activity against those targets. The results suggest that an ensemble receptor-based protocol displays a stronger discriminating power between active and inactive molecules as compared to its standard single rigid receptor counterpart. Moreover, such a protocol can be engineered not only to enrich a higher number of active compounds, but also to enhance their chemical diversity. Finally, some clear indications can be gathered on how to select a subset of receptor conformations that is most likely to provide the best performance in a real life scenario.

Systematic Exploitation of Multiple Receptor Conformations for Virtual Ligand Screening / Bottegoni G.; Rocchia W.; Rueda M.; Abgyan R.; Cavalli A. - In: PLOS ONE. - ISSN 1932-6203. - STAMPA. - 6:(2011), pp. e18845-e18845. [10.1371/journal.pone.0018845]

Systematic Exploitation of Multiple Receptor Conformations for Virtual Ligand Screening

CAVALLI, ANDREA
2011

Abstract

The role of virtual ligand screening in modern drug discovery is to mine large chemical collections and to prioritize for experimental testing a comparatively small and diverse set of compounds with expected activity against a target. Several studies have pointed out that the performance of virtual ligand screening can be improved by taking into account receptor flexibility. Here, we systematically assess how multiple crystallographic receptor conformations, a powerful way of discretely representing protein plasticity, can be exploited in screening protocols to separate binders from non-binders. Our analyses encompass 36 targets of pharmaceutical relevance and are based on actual molecules with reported activity against those targets. The results suggest that an ensemble receptor-based protocol displays a stronger discriminating power between active and inactive molecules as compared to its standard single rigid receptor counterpart. Moreover, such a protocol can be engineered not only to enrich a higher number of active compounds, but also to enhance their chemical diversity. Finally, some clear indications can be gathered on how to select a subset of receptor conformations that is most likely to provide the best performance in a real life scenario.
2011
Systematic Exploitation of Multiple Receptor Conformations for Virtual Ligand Screening / Bottegoni G.; Rocchia W.; Rueda M.; Abgyan R.; Cavalli A. - In: PLOS ONE. - ISSN 1932-6203. - STAMPA. - 6:(2011), pp. e18845-e18845. [10.1371/journal.pone.0018845]
Bottegoni G.; Rocchia W.; Rueda M.; Abgyan R.; Cavalli A
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/106968
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