In doing so, we opted to use the approach implemented in CREST 48 code which uses extensive sampling based on the much faster and yet reliable semi-empirical extended tight-binding method (GFN2-xTB) to generate 3D conformations. The semi-empirical energies and structures are thought to be more accurate than classical force fields, accounting for electronic effects, rare functional groups, and bond-breaking/formation of labile bonds . Moreover, the CREST search algorithm is based on metadynamics (MTD), a well-established thermodynamic sampling approach that can efficiently explore the low-energy search space. Conformers are generated in an iterative manner of MTD and GFN2-xTB optimization, where those geometries are added to the conformer rotamer ensemble (CRE) that overcome certain energy (>12.0 kcal/mol) and root-mean-square deviation (∆R > 0.1 Å) thresholds concerning the input structure. The procedure is restarted using the conformer as input if a new conformer has a lower energy than the input structure. The three conformers of lowest energy undergo two normal molecular dynamics (MD) simulations at 400K and 500K, which are used to sample low-energy barrier crossings, such as simple torsional motions. Finally, a genetic Z-matrix crossing algorithm is used and the results are added to the CRE. Then, a normal-type convergence optimization separates the geometries into conformers, rotamers, and duplicates, where duplicates are deleted and conformers and rotamers added to the CRE. Both geometry optimization and conformational search calculations were carried out considering implicit water described by the Generalized Born (GB) model augmented with the hydrophobic solvent accessible surface area term (GBSA) . Finally, we obtained 2, 242, 490 conformers for the initial set of 2, 635 molecules.