Discovery of CNS-Like D3R-Selective Antagonists Using 3D Pharmacophore Guided Virtual Screening.

June Lee,Mi-hyun Kim,Sung Cho

doi:10.3390/molecules23102452

Abstract

The dopamine D3 receptor is an important CNS target for the treatment of a variety of neurological diseases. Selective dopamine D3 receptor antagonists modulate the improvement of psychostimulant addiction and relapse. In this study, five and six featured pharmacophore models of D3R antagonists were generated and evaluated with the post-hoc score combining two survival scores of active and inactive. Among the Top 10 models, APRRR215 and AHPRRR104 were chosen based on the coefficient of determination (APRRR215: R2training = 0.80; AHPRRR104: R2training = 0.82) and predictability (APRRR215: Q2test = 0.73, R2predictive = 0.82; AHPRRR104: Q2test = 0.86, R2predictive = 0.74) of their 3D-quantitative structure–activity relationship models. Pharmacophore-based virtual screening of a large compound library from eMolecules (>3 million compounds) using two optimal models expedited the search process by a 100-fold speed increase compared to the docking-based screening (HTVS scoring function in Glide) and identified a series of hit compounds having promising novel scaffolds. After the screening, docking scores, as an adjuvant predictor, were added to two fitness scores (from the pharmacophore models) and predicted Ki (from PLSs of the QSAR models) to improve accuracy. Final selection of the most promising hit compounds were also evaluated for CNS-like properties as well as expected D3R antagonism.

Highlights

Dopamine receptors are a class of G protein-coupled receptors in the central nervous system (CNS).There are at least five subtypes of dopamine receptors: D1R, D2R, D3R, D4R and D5R
The imported 3rd set for pharmacophore-based prediction was processed on the basis that the pKi values of active compounds (n = 1111) were >1.5, the pKi values of inactive compounds (n = 1416) were
If a molecule can be fitted inside pharmacophore features, it could be considered a hit molecule based on the fitness score [26]

Summary

Introduction

Dopamine receptors are a class of G protein-coupled receptors in the central nervous system (CNS). There are at least five subtypes of dopamine receptors: D1R, D2R, D3R, D4R and D5R. Many clinically approved drugs targeting the D3R do not show significant selectivity over the D2R and other receptors [9]. We have conducted computer-aided drug identification to investigate D3R-selective antagonists for use in CNS diseases. According to the literature [12], our docking approach identified (as a selective D3R antagonist). D3R antagonist, antagonist, occupied occupied the the deep deep pocket pocket and and was was by found bound to the outer binding pocket to a greater extent [12]. The residue information derived found bound to the outer binding pocket to a greater extent [12].

Superimposed

Definition and Whole

Data Collection and Molecular Docking

Pharmacophore-Based Virtual Screening

Hit Selection

Docking Analysis of D3R Selective Antagonists

Pharmacophore Modeling and 3D-QSAR Models

Representative

Identification of CNS-Like

The Current

Conclusions