Small Molecule IC50 Data Optimization and Alignment

The small molecules used in this study were taken from the literature with their IC₅₀ value [27 (link)] shown in Supplementary Table S1. A total of 36 compounds were retrieved from PubChem (https://pubchem.ncbi.nlm.nih.gov/ as accessed on 15 July 2023) database. Compounds’ 2D structures were optimized using the LigPrep module offered by Schrodinger 2023-2 [50 (link)]. However, the optimization method used default settings, with the OPLS4e force field applied and ionization states neutralized. The intrinsic stereoisomerism of each ligand including its critical chirality was preserved throughout this optimization process. Following optimization, the structures were aligned using the ligand alignment tool. Since every structure is a congeneric series, the software algorithm was used to automatically determine the reference scaffold for the alignment. This is helpful because the program identifies the best scaffold, which serves as a guide. Meanwhile, the biological activity values (IC₅₀) were converted into pIC₅₀ using the above-mentioned Equation (1). Finally, the prepared structures were employed for 3D-QSAR and pharmacophore modeling.