Molecular Entropies of Conformationally Flexible, Gas-Phase Forms of Clinical Drugs: A Black-Box Approach Versus Systematic Sampling

The results of the exhaustive conformational sampling are contrasted with metadynamics-based CREST simulations for a set of 13 gas-phase forms of clinical drug molecules retrieved from the CD25 dataset. [Chem. Sci. 2021, 12 (19), 6551] The GFN1- and GFN2-xTB methods complement each other in the identification of the most stable conformer. The GFN-FF performs worse due to fundamental differences between the force field and the density functional theory (DFT) potential energy surfaces. Conformational entropies (S_conf) from the systematic search as well as from the standard CREST entropy mode calculations with the single-point Hessian (SPH) deactivated are in reasonable agreement with their molecular dynamics counterparts that account for torsional correlation [J. Chem. Theory Comput. 2022, 18, 7166-7178]. The CREST entropy mode evaluations on the DFT-refined geometries using the activated SPH routine yield too large S_conf values for some species due to the overestimation of the Boltzmann entropy averaging ( ${\overline{S}}^{°}-S_1^{°}$ ) contribution.