期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 15, 页码 -出版社
MDPI
DOI: 10.3390/ijms22158112
关键词
novel sigma-1 receptor ligands; virtual screening protocol; ensemble docking; radioligand binding assay
资金
- National Research Development and Innovation Office (NKFIH) [GINOP-2.3.2-15-2016-00060, GINOP-2.3.2-15-2016-00034]
A new ensemble docking-based virtual screening protocol utilizing both agonist and antagonist bound S1R structures was developed in this study, leading to the identification of three novel high affinity S1R ligands, one of which exhibited notable S1R/S2R selectivity.
Sigma-1 receptor (S1R) is an intracellular, multi-functional, ligand operated protein that also acts as a chaperone. It is considered as a pluripotent drug target in several pathologies. The publication of agonist and antagonist bound receptor structures has paved the way for receptor-based in silico drug design. However, recent studies on this subject payed no attention to the structural differences of agonist and antagonist binding. In this work, we have developed a new ensemble docking-based virtual screening protocol utilizing both agonist and antagonist bound S1R structures. This protocol was used to screen our in-house compound library. The S1R binding affinities of the 40 highest ranked compounds were measured in competitive radioligand binding assays and the sigma-2 receptor (S2R) affinities of the best S1R binders were also determined. This way three novel high affinity S1R ligands were identified and one of them exhibited a notable S1R/S2R selectivity.
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