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Multiple Structures for Virtual Ligand Screening: Defining Binding Site Properties-Based Criteria to Optimize the Selection of the Query
journal contribution
posted on 2013-02-25, 00:00 authored by Nesrine Ben Nasr, Hélène Guillemain, Nathalie Lagarde, Jean-François Zagury, Matthieu MontesStructure based virtual ligand screening (SBVLS) methods
are widely
used in drug discovery programs. When several structures of the target
are available, protocols based either on single structure docking
or on ensemble docking can be used. The performance of the methods
depends on the structure(s) used as a reference, whose choice requires
retrospective enrichment studies on benchmarking databases which consume
additional resources. In the present study, we have identified several
trends in the properties of the binding sites of the structures that
led to the optimal performance in retrospective SBVLS tests whatever
the docking program used (Surflex-dock or ICM). By assessing their
hydrophobicity and comparing their volume and opening, we show that
the selection of optimal structures should be possible with no requirement
of prior retrospective enrichment studies. If the mean binding site
volume is lower than 350 A3, the structure with the smaller
volume should be preferred. In the other cases, the structure with
the largest binding site should be preferred. These optimal structures
may be either selected for a single structure docking strategy or
an ensemble docking strategy. When constructing an ensemble, the opening
of the site might be an interesting criterion additionaly to its volume
as the most closed structures should not be preferred in the large
systems. These “binding site properties-based” guidelines
could be helpful to optimize future prospective drug discovery protocols
when several structures of the target are available.
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retrospective enrichment studiesbinding sitesligand screeningensemble docking strategyensemble dockingcriterion additionalystructure dockingdrug discovery protocolsVirtual Ligand Screeningretrospective SBVLS testsbinding site volumeICMbenchmarking databasesdocking programMultiple Structuresdrug discovery programsbinding sitestructure docking strategy
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