Increasing small molecule drug developability in sub-optimal chemical space

Using compounds occupying four distinct clog P/molecular weight regions that define optimal and suboptimal chemical space, and a developability score derived from solubility, permeability, protein binding and 3A4 inhibition screening data, OPLS regression models were constructed to determine which physico-chemical properties were most correlated with developability. The results suggested that whilst certain molecule properties were important for developability across all chemical space, such as [clog D + aromatic ring count], [clog D + (aromatic atom count - sp(3) carbon count)] and [sp(3) carbon count/total carbon count], others such as heteroaliphatic ring count, positive ionisable group count and H-bond donor character exhibited varying degrees of importance depending on the clog P/M-w region.