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Summary: Systematic Exploitation of Multiple Receptor
Conformations for Virtual Ligand Screening
Giovanni Bottegoni1
, Walter Rocchia1
, Manuel Rueda2
, Ruben Abagyan2
, Andrea Cavalli1,3
*
1 Department of Drug Discovery and Development (D3), Istituto Italiano di Tecnologia, Genova, Italy, 2 Skaggs School of Pharmacy and Pharmaceutical Sciences,
University of California San Diego, La Jolla, California, United States of America, 3 Dipartimento di Scienze Farmaceutiche, Universita` di Bologna, Bologna, Italy
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.
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