Opioids with analgesic potential: A chemometric experiment aimed at Chemistry Education

Abstract

Opioids with different degrees of inhibitory activity were investigated by means of a chemometric experiment designed for the various levels of Chemistry Education. The crystallographic structure of mitragynine taken from the literature was completely optimized with different theories (methods)/basis sets and, through the chemometric techniques of exploratory data analysis - Principal Component Analysis and Hierarchical Cluster Analysis - the most appropriate theory/basis set for the development of the experiment was defined (B3LYP/6-31G**). The optimized mitragynine, in the most stable conformation, led to the construction of 3D structures of the other opioids, which were also subjected to complete optimizations and calculations of molecular properties in the lowest energy conformations. The referred properties (molecular descriptors) through Exploratory Data Analysis - Principal Component Analysis (PCA) and Hierarchical Cluster Analysis (HCA) - allowed the separation of ten (10) opioids (training set) into two classes: the most active opioid class (MAO), compounds 1, 2, 5, 6, 9, and 10, and the least active opioid class (LAO), compounds 3, 4, 7, and 8. The application of the classification methods: K-nearest neighbor method (KNN method) and Stepwise Discriminant Analysis (SDA) to the training set ratified its separation into the MAO class and LAO class. The insights obtained in the chemometric treatment and chemical intuition led to the proposition of nine (9) new opioids (validation set), whose scrutiny of the constructed models - PCA model, HCA model, KNN model and SDA model - indicated six (6) new opioids derived from mitragynine with analgesic potential for synthesis and biological tests.