6 research outputs found
Multiple Structures for Virtual Ligand Screening: Defining Binding Site Properties-Based Criteria to Optimize the Selection of the Query
Structure 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 A<sup>3</sup>, 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 ābinding site properties-basedā guidelines
could be helpful to optimize future prospective drug discovery protocols
when several structures of the target are available
Multiple Structures for Virtual Ligand Screening: Defining Binding Site Properties-Based Criteria to Optimize the Selection of the Query
Structure 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 A<sup>3</sup>, 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 ābinding site properties-basedā guidelines
could be helpful to optimize future prospective drug discovery protocols
when several structures of the target are available
Multiple Structures for Virtual Ligand Screening: Defining Binding Site Properties-Based Criteria to Optimize the Selection of the Query
Structure 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 A<sup>3</sup>, 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 ābinding site properties-basedā guidelines
could be helpful to optimize future prospective drug discovery protocols
when several structures of the target are available
Multiple Structures for Virtual Ligand Screening: Defining Binding Site Properties-Based Criteria to Optimize the Selection of the Query
Structure 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 A<sup>3</sup>, 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 ābinding site properties-basedā guidelines
could be helpful to optimize future prospective drug discovery protocols
when several structures of the target are available
NRLiSt BDB, the Manually Curated Nuclear Receptors Ligands and Structures Benchmarking Database
Nuclear receptors (NRs) constitute
an important class of drug targets.
We created the most exhaustive NR-focused benchmarking database to
date, the NRLiSt BDB (NRs ligands and structures benchmarking database).
The 9905 compounds and 339 structures of the NRLiSt BDB are ready
for structure-based and ligand-based virtual screening. In the present
study, we detail the protocol used to generate the NRLiSt BDB and
its features. We also give some examples of the errors that we found
in ChEMBL that convinced us to manually review all original papers.
Since extensive and manually curated experimental data about NR ligands
and structures are provided in the NRLiSt BDB, it should become a
powerful tool to assess the performance of virtual screening methods
on NRs, to assist the understanding of NRās function and modulation,
and to support the discovery of new drugs targeting NRs. NRLiSt BDB
is freely available online at http://nrlist.drugdesign.fr
Antiproliferative Activity of <i>trans-</i>Avicennol from <i>Zanthoxylum chiloperone</i> var. <i>angustifolium</i> against Human Cancer Stem Cells
<i>Zanthoxylum chiloperone</i> var. <i>angustifolium</i> root bark was studied with the aim of finding
novel molecules able
to overcome cancer stem cell chemoresistance. Purification of a methanol-soluble
extract resulted in the isolation of a known pyranocoumarin, <i>trans</i>-avicennol (<b>1</b>). Compound <b>1</b> demonstrated antiproliferative activity on glioma-initiating cells,
whereas it was inactive on human neural stem cells. <i>trans</i>-Avicennol (<b>1</b>) activated the MAPK/ERK pathway and was
also evaluated for its ability to inhibit the enzyme indoleamine-2,3-dioxygenase