Refinement of Computational Access to Molecular Physicochemical Properties: From Ro5 to bRo5

There is a need of computational tools to rank bRo5 drug
candidates
in the very early phases of drug discovery when chemical matter is
unavailable. In this study, we selected three compounds: (a) a Ro5
drug (Pomalidomide), (b) a bRo5 orally available drug (Saquinavir),
and (c) a polar PROTAC (CMP 98) to focus on computational access to
physicochemical properties. To provide a benchmark, the three compounds
were first experimentally characterized for their lipophilicity, polarity,
IMHBs, and chameleonicity. To reproduce the experimental information
content, we generated conformer ensembles with conformational sampling
and molecular dynamics in both water and nonpolar solvents. Then we
calculated Rgyr, 3D PSA, and IMHB number. An innovative pool of strategies
for data analysis was then provided. Overall, we report a contribution
to close the gap between experimental and computational methods for
characterizing bRo5 physicochemical properties.