Article
Version 1
Preserved in Portico This version is not peer-reviewed
Discovery of CNS-Like D3R- Selective Antagonists Using 3D Pharmacophore Guided Virtual Screening
Version 1
: Received: 22 July 2018 / Approved: 23 July 2018 / Online: 23 July 2018 (14:09:10 CEST)
A peer-reviewed article of this Preprint also exists.
Lee, J.H.; Cho, S.J.; Kim, M.-H. Discovery of CNS-Like D3R-Selective Antagonists Using 3D Pharmacophore Guided Virtual Screening. Molecules 2018, 23, 2452. Lee, J.H.; Cho, S.J.; Kim, M.-H. Discovery of CNS-Like D3R-Selective Antagonists Using 3D Pharmacophore Guided Virtual Screening. Molecules 2018, 23, 2452.
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 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 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.
Keywords
Pharmacophore; 3D-QSAR; virtual screening; D3R selective antagonist; molecular docking; CNS-like
Subject
Chemistry and Materials Science, Medicinal Chemistry
Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Comments (0)
We encourage comments and feedback from a broad range of readers. See criteria for comments and our Diversity statement.
Leave a public commentSend a private comment to the author(s)
* All users must log in before leaving a comment