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

Szabolcs Dvorácskó,Botond Penke,Ferenc Bogár,Márta Palkó,Zita Zalán,Csaba Tömböly,Lívia Fülöp,Ferenc Fülöp,László Lázár

doi:10.3390/ijms22158112

Abstract

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.

Highlights

Sigma receptor was first identified in 1976 by Martin et al as an opioid receptor subtype [1]
We used an active set of twenty diverse compounds selected from 190 Sigma-1 receptor (S1R) ligands with subnanomolar affinity collected from the BINDINGDB database [52]
Applying an enrichment-based model selection procedure, we have established a minimal ensemble virtual screening (VS) protocol based on the chains with the best enrichment from the antagonist bound-5HK1 and the agonist-bound 6DK1 S1R structures

Summary

Introduction

Sigma receptor was first identified in 1976 by Martin et al as an opioid receptor subtype [1] It turned out in the early eighties that the pharmacological character of sigma receptor diverges from the other opioid receptors [2,3]. This and the subsequent scientific efforts led to the identification of the sigma non-opioid intracellular receptor family [4] with its two members, sigma-1 (S1R) and sigma-2 (S2R) receptors [5]. The receptor can be dynamically translocated inside the cells It is an intracellular, multi-functional, ligand operated protein that acts as a chaperone [6]

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