In the context of open-source applications, we used the default settings provided by the developers of the methods. In the case of ETKDG (from RDKit), the conformations were generated and then optimized using the MMFF94 force field. The 'rdkit.Chem.AllChem' module was utilized to generate conformations through a Python script. The number of generated conformations was set to 1000 by invoking the 'EmbedMultipleConfs' keyword, with the RMS threshold set to 0.1 kcal mol -1 Å -1 (pruneRmsThresh = 0.1). The 'randomSeed' keyword was employed to acquire a seed for the random number generator. Following this, the generated conformations underwent optimization using the MMFF94 force field, and the resulting optimized coordinates and energy were stored for subsequent analysis. Balloon also uses energy minimization employing the MMFF94 (file name-'MMFF94.mff') force field, which is defined using the '-forcefield' ('-f') setting in Balloon, and the input and output file formats are in SDF.