Published 2020
| Version v1
Publication
Exploring the selectivity profile of sigma receptor ligands by molecular docking and pharmacophore analyses.
Creators
Contributors
Others:
Description
sRs),
Background: Sigma receptors (
initially classified as an additional class of opioid receptors, are
now recognized as a unique entity with no homology to opioid receptors divided into two distinct
s1R
s2R.
subtypes namely
and
.1R-targeting ligands have been conceived and explored for the
s2R
treatment of various neurodegenerative disorders and neuropathic pain. Activation of the
appears
to be involved in the regulation of cellular proliferation and cell death.
s1R
Objective: Up to now, the rational design of novel
ligands was efficiently guided by
computational methods, especially relying on homology modeling studies. Conversely, the limited
s2R-
number of in silico studies was applied in the search of
targeting compounds. Herein we explored
by computational methods several series of .1R ligands featuring variable selectivity profile towards
s1R
s
and
R in order to gain useful information guiding the rational design of more selective ligands.
.
s1R,
Methods: Based on the recent X-ray crystallographic structure of the human
deepening
sR
molecular docking studies on different series of
ligands have been performed. These calculations
have been followed by molecular dynamic simulations (MD) and by two pharmacophore analyses,
s1R
s
taking into account the activity levels towards
and
.R.
Results: Structure-based studies revealed key contacts to be achieved in order to guide selectivity of
s1R
-targeting compounds while the two pharmacophore models described the main features turning in
s1R
s2R
effective
or
ligands.
Conclusion: The applied computational approach allowed a more comprehensive exploration of the
structure-activity relationship (SAR) within the herein analyzed .R ligands, deriving useful guidelines
for the rational design of more selective compounds.
Additional details
Identifiers
- URL
- http://hdl.handle.net/11567/1037691
- URN
- urn:oai:iris.unige.it:11567/1037691