CANDID-CNS: AI Unlocks Stereochemistry and Beyond Rule of 5 to Predict CNS Penetration of Small Molecules.

ABSTRACT: Neuroscience is the most difficult therapeutic area for pharmaceutical drug discovery. The blood-brain barrier (BBB) prevents ∼100% of large molecules and >98% of small molecules from penetrating the central nervous system (CNS). Most small molecule drugs designed for the CNS are Rule of 5 (Ro5) molecules. Thus, Beyond Rule of 5 (bRo5) molecules, which have significant potential to act on especially difficult drug targets and indications, represent an untapped chemical class for novel CNS therapeutics. However, bRo5 small molecules face three key challenges: (i) exclusion from most medicinal chemistry drug designs, (ii) difficulty penetrating the BBB, and (iii) inability of existing computational methods to predict the CNS penetration of bRo5 molecules. In addition, the stereochemistry of

SUBMITTER: Collins JW 

PROVIDER: S-EPMC12690596 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature