Two- and Three-dimensional Quantitative Structure-activity Relationship Models Based on Conformer Structures

In three-dimensional (3D)-quantitative structure-activity relationship (QSAR) analysis, the chemical structure of a studied molecule is typically optimized assuming its presence in a vacuum environment. However, in practical scenarios, the environment of even the most stable molecules contains water, proteins, and other species; therefore, their actual structures significantly differ from those in vacuum and have multiple structures. Herein, both two-dimensional and 3D molecular descriptors, which accepted the existence of multiple conformers, were calculated, and a conformer-based 3D-QSAR model (C3D-QSAR) that considered the chemical structures of conformers was developed. The prediction accuracy of the C3D-QSAR method determined by analyzing the data sets obtained for the angiotensin-converting enzyme and dihydrofolate reductase inhibitors was found to be higher than those of the existing QSAR models.