SCB-01A

Prediction of compound properties from structure via quantitative structure-activity relationship and machine-learning approaches is an important computational chemistry task in small-molecule drug research. Though many such properties are dependent on three-dimensional structures or even conformer ensembles, the majority of models are based on descriptors derived from two-dimensional structures. Here we present results from a thorough benchmark study of force field, semiempirical, and density functional methods for the calculation of conformer energies in the gas phase and water solvation as a foundation for the correct identification of relevant low-energy conformers. We find that the tight-binding ansatz GFN-xTB shows the lowest error metrics and highest correlation to the benchmark PBE0-D3(BJ)/def2-TZVP in the gas phase for the computationally fast methods and that in solvent OPLS3 becomes comparable in performance. MMFF94, AM1, and DFTB+ perform worse, whereas the performance-optimized but far more expensive functional PBEh-3c yields energies almost perfectly correlated to the benchmark and should be used whenever affordable. On the basis of our findings, we have implemented a reliable and fast protocol for the identification of low-energy conformers of drug-like molecules in water that can be used for the quantification of strain energy and entropy contributions to target binding as well as for the derivation of conformer-ensemble-dependent molecular descriptors.

We present a composite procedure for the quantum‐chemical computation of spin–spin‐coupled 1H NMR spectra for general, flexible molecules in solution that is based on four main steps, namely conformer/rotamer ensemble (CRE) generation by the fast tight‐binding method GFN‐xTB and a newly developed search algorithm, computation of the relative free energies and NMR parameters, and solving the spin Hamiltonian. In this way the NMR‐specific nuclear permutation problem is solved, and the correct spin symmetries are obtained. Energies, shielding constants, and spin–spin couplings are computed at state‐of‐the‐art DFT levels with continuum solvation. A few (in)organic and transition‐metal complexes are presented, and very good, unprecedented agreement between the theoretical and experimental spectra was achieved. The approach is routinely applicable to systems with up to 100–150 atoms and may open new avenues for the detailed (conformational) structure elucidation of, for example, natural products or drug molecules.