Novel High Affinity Sigma-1 Receptor Ligands from Minimal Ensemble Docking-Based Virtual Screening

Dvorácskó, Szabolcs [Dvorácskó, Szabolcs (biokémia), author] Institute of Biochemistry; Lázár, László [Lázár, László (Szerves kémia, gy...), author] Department of Pharmaceutical Chemistry (SZTE / FP); Fülöp, Ferenc [Fülöp, Ferenc (Kémia), author] Department of Pharmaceutical Chemistry (SZTE / FP); Palkó, Márta [Palkó, Márta (Gyógyszerkémia, s...), author] Department of Pharmaceutical Chemistry (SZTE / FP); Zalán, Zita [Zalán, Zita (Szerves kémia, gy...), author] Department of Pharmaceutical Chemistry (SZTE / FP); Penke, Botond [Penke, Botond (Neurodegeneráció,...), author] Department of Medical Chemistry (SZTE / ASZMS); Fülöp, Lívia ✉ [Fülöp, Lívia (Neurodegeneratív ...), author] Department of Medical Chemistry (SZTE / ASZMS); Tömböly, Csaba [Tömböly, Csaba (Peptidkémia, radi...), author] Institute of Biochemistry; Bogár, Ferenc ✉ [Bogár, Ferenc (Molekulamodellezés), author] Department of Medical Chemistry (SZTE / ASZMS); MTA-SZTE Biomimetic Systems Research Group (SZTE / ASZMS / DMC)

English Article (Journal Article) Scientific
Published: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 1661-6596 1422-0067 22 (15) Paper: 8112 , 17 p. 2021
  • SJR Scopus - Spectroscopy: D1
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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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2025-06-16 02:07