Here, we exhaustively analyzed the sampling method implemented in four different codes: CREST 48 , Maestro, Omega and RDKit . The last three codes are of standard use in cheminformatics, primarily relying on stochastic algorithms for their application. They explore the conformational space of molecules very sparsely through a combination of pre-defined distances and stochastic samples and can miss many low-energy conformations. Moreover, in most standalone applications, conformer energies are typically computed using classical force fields without the incorporation of solvent models, which made these values rather inaccurate (for more details of these methods see Sec. 2 of the SI). On the contrary, CREST code utilizes a robust sampling strategy, leveraging the semi-empirical extended tight-binding method (GFN2-xTB) , supplemented by the GBSA implicit solvent model of water, in order to generate more reliable 3D conformations compared to those obtained using classical force fields (see "Methods"). The conformational search workflow implemented in CREST provides access to a more extensive exploration of low-and high-energy conformers, generating molecular structures inaccessible by distance geometry methods (see Fig. ) .