Harmonic Vibrational Frequency Simulation of Pharmaceutical Molecules via a Novel Multi-Molecular Fragment Interception Method

By means of a computational method based on Density Functional Theory (DFT), using commercially available software, a novel method for simulating equilibrium geometry harmonic vibrational frequencies is proposed. Finasteride, Lamivudine, and Repaglinide were selected as model molecules to study the adaptability of the new method. Three molecular models, namely the single-molecular, central-molecular, and multi-molecular fragment models, were constructed and calculated by Generalized Gradient Approximations (GGAs) with the PBE functional via the Material Studio 8.0 program. Theoretical vibrational frequencies were assigned and compared to the corresponding experimental data. The results indicated that the traditional single-molecular calculation and scaled spectra with scale factor exhibited the worst similarity for all three pharmaceutical molecules among the three models. Furthermore, the central-molecular model with a configuration closer to the empirical structure resulted in a reduction of mean absolute error (MAE) and root mean squared error (RMSE) in all three pharmaceutics, including the hydrogen-bonded functional groups. However, the improvement in computational accuracy for different drug molecules using the central-molecular model for vibrational frequency calculation was unstable. Whereas, the new multi-molecular fragment interception method showed the best agreement with experimental results, exhibiting MAE and RMSE values of 8.21 cm(−1) and 18.35 cm(−1) for Finasteride, 15.95 cm(−1) and 26.46 cm(−1) for Lamivudine, and 12.10 cm(−1) and 25.82 cm(−1) for Repaglinide. Additionally, this work provides comprehensive vibrational frequency calculations and assignments for Finasteride, Lamivudine, and Repaglinide, which have never been thoroughly investigated in previous research.