@conference{
author = "Đikić, Teodora and Vučićević, Jelica and Laurila, Jonne and Radi, Marco and Veljković, Nevena and Xhaard, Henri",
year = "2021",
abstract = "Centrally acting hypotensive imidazoline derivatives are agonists of α2-adrenoceptors and non-adrenergic
I1-imidazoline receptors. Based on the finding that a central antihypertensive agent with high affinity for
I1-type imidazoline receptors – rilmenidine, shows cytotoxic effects on cultured cancer cell lines, it has been
suggested that imidazoline receptors agonists might have a therapeutic potential in cancer therapy. Never-
theless, rilmenidine itself does not represent a suitable candidate because of possible side effect caused by
activation of α 2 -adrenergic receptors. In our previous work, several novel rilmenidine-derived compounds
with anticancer potential and without an agonistic activity on α 2
-adrenoceptor were identified. Taking into
consideration that human α2
-adrenergic receptors belong to the rhodopsin-like class A of G protein-coupled
receptors (GPCRs), the biggest group of drug targets, that share structure similarity, it is reasonable to assume
that these ligands might have the affinity on some other receptors from the same class.
To investigate potential additional targets for novel imidazoline I1 agonists a reverse docking protocol on
107 GPCRs, using 63 imidazoline ligands and their 670 decoys was prepared. Unlike typical molecular dock-
ing protocol, where series of small molecules are docked in one macromolecular target, in case of reverse
docking a small-molecule is docked in the set of potential target proteins. Due to the availability of crystal
structures all of the included GPCRs, were in inactive state, and therefore suitable for identification of the
receptors antagonized by imidazoline ligands. Based on ROC curves and Enrichment Factors, 20 potential
off-target GPCRs were selected. To better assess the affinity of imidazoline derivatives for chosen receptors,
an additional docking study was performed, and docking scores of imidazolines were compared with docking
scores of known antagonists. Finally, to verify in silico results, three ligands with high scores and tree ligands
with low scores were tested for antagonistic activity on α2
-adrenergic receptors.
The protocol described here could be applied on all the small molecules, for the detection of potential inter-
actions with GPCRs of class A, in the early stage of drug design process. Additionally, this protocol is easily
expandable, by adding novel receptors/subfamily of receptors as soon as the crystal structures and/or 3D
models become available.",
publisher = "Department of Biology and Ecology Faculty of Sciences University of Novi Sad, Serbia",
journal = "Biologia Serbica",
title = "Imidazolines: In silico off-target fishing in the class A of G protein-coupled receptors",
volume = "43",
number = "1, Special Edition",
pages = "88-88",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4863"
}
