Proteins are a primary target for developing drug therapies to address certain diseases. Understanding the link between ligand characteristics, such as molecular hardness, and binding affinity could provide a more effective way to design drugs for use in treating disease. Thus, this study involved the subset of diverse proteins (Acetylcholinesterase, AmpC Beta-Lactamase, Cytochrome P450 3A4, Glucocorticoid Receptor, HIV Reverse Transcriptase, and Serine/Threonine Kinase 1) from the Database of Useful Decoys: Enhanced (DUD-E), with a focus on ligand binding sites. The active sites of these proteins were examined with computational docking of using over 50 molecules per target. Separately, ground-state electronic structure calculations were also carried out to determine the molecular hardness of each ligand. By integrating these results, we aim to develop a quantitative scale of active site hardness that enhances the predictability of ligand-binding affinity.
