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Molecules 2018, 23(9), 2183; https://doi.org/10.3390/molecules23092183

Discovery of High-Affinity Cannabinoid Receptors Ligands through a 3D-QSAR Ushered by Scaffold-Hopping Analysis

1
Department of Drug Sciences, University of Catania, V.le A. Doria, 95125 Catania, Italy
2
Department of Chemical Sciences, University of Catania, V.le A. Doria, 95125 Catania, Italy
3
Institute of Pharmaceutical Science, King’s College London, Stamford Street, London SE1 9NH, UK
4
King’s Forensics, School of Population Health & Environmental Sciences, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK
In memory of Professor Carmela Spatafora, a friend, colleague and distinguished scientist, on the second anniversary of her premature death.
*
Authors to whom correspondence should be addressed.
Received: 23 August 2018 / Revised: 26 August 2018 / Accepted: 28 August 2018 / Published: 30 August 2018
(This article belongs to the Special Issue QSAR and QSPR: Recent Developments and Applications)
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Abstract

Two 3D quantitative structure–activity relationships (3D-QSAR) models for predicting Cannabinoid receptor 1 and 2 (CB1 and CB2) ligands have been produced by way of creating a practical tool for the drug-design and optimization of CB1 and CB2 ligands. A set of 312 molecules have been used to build the model for the CB1 receptor, and a set of 187 molecules for the CB2 receptor. All of the molecules were recovered from the literature among those possessing measured Ki values, and Forge was used as software. The present model shows high and robust predictive potential, confirmed by the quality of the statistical analysis, and an adequate descriptive capability. A visual understanding of the hydrophobic, electrostatic, and shaping features highlighting the principal interactions for the CB1 and CB2 ligands was achieved with the construction of 3D maps. The predictive capabilities of the model were then used for a scaffold-hopping study of two selected compounds, with the generation of a library of new compounds with high affinity for the two receptors. Herein, we report two new 3D-QSAR models that comprehend a large number of chemically different CB1 and CB2 ligands and well account for the individual ligand affinities. These features will facilitate the recognition of new potent and selective molecules for CB1 and CB2 receptors. View Full-Text
Keywords: cannabinoid receptor; CB1 and CB2; 3D-QSAR; scaffold hopping; virtual screening; Forge and Spark software; bioisosteric replacements cannabinoid receptor; CB1 and CB2; 3D-QSAR; scaffold hopping; virtual screening; Forge and Spark software; bioisosteric replacements
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Floresta, G.; Apirakkan, O.; Rescifina, A.; Abbate, V. Discovery of High-Affinity Cannabinoid Receptors Ligands through a 3D-QSAR Ushered by Scaffold-Hopping Analysis. Molecules 2018, 23, 2183.

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