Clustering of atoms relative to vector space in the Z-matrix coordinate system and ‘graphical fingerprint’ analysis of 3D pharmacophore structure

The behavior of a molecule within its environment is governed by chemical fields present in 3D space. However, beyond local descriptors in 3D, the conformations a molecule assumes, and the resulting clusters also play a role in influencing structure–activity models. This study focuses on the clustering of atoms according to the vector space of four atoms aligned in the Z-Matrix Reference system for molecular similarity. Using 3D-QSAR analysis, it was aimed to determine the pharmacophore groups as interaction points in the binding region of the β2-adrenoceptor target of fenoterol stereoisomers. Different types of local reactive descriptors of ligands have been used to elucidate points of interaction with the target. Activity values for ligand-receptor interaction energy were determined using the Levenberg–Marquardt algorithm. Using the Molecular Comparative Electron Topology method, the 3D pharmacophore model (3D-PhaM) was obtained after aligning and superimposing the molecules and was further validated by the molecular docking method. Best guesses were calculated with a non-output validation (LOO-CV) method. Finally, the data were calculated using the ‘graphic fingerprint’ technique. Based on the eLKlopman (Electrostatic LUMO Klopman) descriptor, the Q2 value of this derivative set was calculated as 0.981 and the R2ext value is calculated as 0.998. © The Author(s) 2024.