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 (Sconf) 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 Sconf values for some species due to the overestimation of the Boltzmann entropy averaging ( S ¯ ° - S 1 ° ) contribution.