Title

Pharmacophore and docking-based sequential virtual screening for the identification of novel Sigma 1 receptor ligands

Authors

Mubarak A. Alamri^*,1 & Mohammed A. Alamri²

Affiliation

¹Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj 11942, Saudi Arabia; ²Department of Pharmacology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj 11942, Saudi Arabia.

Email

Mubarak A. Alamri - E-mail: m.alamri@psau.edu.sa; *Corresponding author

Article Type

Research Article

Date

Received August 25, 2019; Accepted August 31, 2019; Published September 10, 2019

Sigma 1 receptor (σ1), a small transmembrane protein expressed in most human cells participates in modulating the function of other membrane proteins such as G protein coupled receptors and ion channels. Several ligands targeting this receptor are currently in clinical trials for the treatment of Alzheimer's disease, ischemic stroke and neuro-pathic pain. Hence, this receptor has emerged as an attractive target for the treatment of neuro-pathological diseases with unmet medical needs. It is of interest to identify and characterise novel σ1 receptor ligands with different chemical scaffolds using computer-aided drug designing approach. In this work, a GPCR-focused chemical library consisting of 8543 compounds was screened by pharmacophore and docking-based virtual screening methods using LigandScout 4.3 and Autodock Vina 1.1.2 in PyRx 0.8, respectively. The pharmacophore model was constructed based on the interactions of a selective agonist and another antagonist ligand with high binding affinity to the human σ1receptors. Candidate compounds were filtered sequentially by pharmacophore-fit scores, docking energy scores, drug-likeness filters and ADMET properties. The binding mode and pharmacophore mapping of candidate compounds were analysed by Autodock Vina 1.1.2 and LigandScout 4.3 programs, respectively. A pharmacophore model composed of three hydrophobic and positive ionizable features with recognized geometry was built and used as a 3D query for screening a GPCR-focused chemical library by LigandScout 4.3 program. Among the screened 8543 compounds, 159 candidate compounds were obtained from pharmacophore-based screening. 45 compounds among them bound to σ1receptor with high binding-affinity scores in comparison to the co-crystallized ligand. Amongst these, top five candidate compounds with excellent druglikeness and ADMET properties were selected. These five candidate compounds may act as potential σ1 receptor ligands.

Keywords

Sigma 1, Sigma 2, pharmacophore modelling, screening, molecular docking

Citation

Alamri & Alamri, Bioinformation 15(8): 586-595 (2019)

Edited by

P Kangueane

ISSN

0973-2063

Publisher

Biomedical Informatics

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.