Oncology exploration: Charting cancer medicinal chemistry space

Approaches for the experimental determination of protein-ligand molecular interactions are reliant on the quality of the compounds being tested. The application of large, randomly designed combinatorial libraries has given way to the creation of more-focused 'drug-like' libraries. Prior to synthesis, we wish to screen the potential compounds to remove undesired chemical moieties and to be within a required range of physiochemical properties. We have used a principal-component analysis (PCA) computational approach to analyze the 3D descriptor space of active and non-active (hit-like) cancer medicinal chemistry compounds. We define hit-like those molecules passing the unmodified OpenEye FILTER program. Our analysis indicates that these compounds occupy quite different regions in space. Cancer-active compounds exist in a much greater volume of space than generic hit-like space and most of them fail the commonly applied filters for orally bioavailable drugs. This is of great significance when designing orally bioavailable cancer target drugs.