Structure-Based Approach for the Prediction of Mu-opioid Binding Affinity of Unclassified Designer Fentanyl-Like Molecules.

Giuseppe Floresta,Antonio Rescifina,Vincenzo Abbate

doi:10.3390/ijms20092311

Giuseppe Floresta, Antonio Rescifina + Show 1 more

Open Access

https://doi.org/10.3390/ijms20092311

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Abstract

Three quantitative structure-activity relationship (QSAR) models for predicting the affinity of mu-opioid receptor (μOR) ligands have been developed. The resulted models, exploiting the accessibility of the QSAR modeling, generate a useful tool for the investigation and identification of unclassified fentanyl-like structures. The models have been built using a set of 115 molecules using Forge as a software, and the quality was confirmed by statistical analysis, resulting in being effective for their predictive and descriptive capabilities. The three different approaches were then combined to produce a consensus model and were exploited to explore the chemical landscape of 3000 fentanyl-like structures, generated by a theoretical scaffold-hopping approach. The findings of this study should facilitate the identification and classification of new μOR ligands with fentanyl-like structures.

Highlights

Opioid receptors are the target proteins of narcotic analgesics, of which morphine is the prototype, and their activation can produce a variety of pharmacological responses [1] that are used for the treatment of different medical conditions [2,3,4]
Some of the identified molecules are temporarily placed by the Drug Enforcement Administration (DEA) in the US Schedule I waiting for complete analyses and data, which can be a time-consuming exercise
The present study explores the development of three quantitative structure-activity relationship (QSAR) models exploitable for the prediction of a ligand affinity to the μOR, and for the identification of new molecules that could efficiently interact with such receptor class

Summary

Introduction

Opioid receptors are the target proteins of narcotic analgesics, of which morphine is the prototype, and their activation can produce a variety of pharmacological responses [1] that are used for the treatment of different medical conditions [2,3,4]. Their pharmacological action had been known long before the morphine itself was discovered, and, in early civilizations, extracts from the Papaver somniferum were widely used as a medicine [5]. Fentanyl is a potent agonist of the μOR, causing the classical analgesic and euphoric pharmacological effects of this class of compounds

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