Molecular properties determining unbound intracellular and extracellular brain exposure of CNS drug candidates

In the present work we sought to gain a mechanistic understanding of the physicochemical properties that influence the transport of unbound drug across the bloodbrain barrier (BBB) as well as the intra- and extracellular drug exposure in the brain. Interpretable molecular descriptors that significantly contribute to the three key neuropharmacokinetic properties related to BBB drug transport (K-p,K-uu,K-brain), intracellular accumulation (K-p,K-uu,K-cell), and binding and distribution in the brain (V-u,V-brain) for a set of 40 compounds were identified using partial least-squares (PLS) analysis. The tailoring of drug properties for improved brain exposure includes decreasing the polarity and/or hydrogen bonding capacity. The design of CNS drug candidates with intracellular targets may benefit from an increase in basicity and/or the number of hydrogen bond donors. Applying this knowledge in drug discovery chemistry programs will allow designing compounds with more desirable CNS pharmacokinetic properties

The Structure of Murine <i>N</i>¹‑Acetylspermine Oxidase Reveals Molecular Details of Vertebrate Polyamine Catabolism

<i>N</i>¹-Acetylspermine oxidase (APAO) catalyzes the conversion of <i>N</i>¹-acetylspermine or <i>N</i>¹-acetylspermidine to spermidine or putrescine, respectively, with concomitant formation of <i>N</i>-acetyl-3-aminopropanal and hydrogen peroxide. Here we present the structure of murine APAO in its oxidized holo form and in complex with substrate. The structures provide a basis for understanding molecular details of substrate interaction in vertebrate APAO, highlighting a key role for an asparagine residue in coordinating the <i>N</i>¹-acetyl group of the substrate. We applied computational methods to the crystal structures to rationalize previous observations with regard to the substrate charge state. The analysis suggests that APAO features an active site ideally suited for binding of charged polyamines. We also reveal the structure of APAO in complex with the irreversible inhibitor MDL72527. In addition to the covalent adduct, a second MDL72527 molecule is bound in the active site. Binding of MDL72527 is accompanied by altered conformations in the APAO backbone. On the basis of structures of APAO, we discuss the potential for development of specific inhibitors

A protein tertiary structure mimetic modulator of the Hippo signalling pathway

10.1038/s41467-020-19224-8Nature Communications111542

Molecular Properties Determining Unbound Intracellular and Extracellular Brain Exposure of CNS Drug Candidates

In the present work we sought to gain a mechanistic understanding of the physicochemical properties that influence the transport of unbound drug across the blood–brain barrier (BBB) as well as the intra- and extracellular drug exposure in the brain. Interpretable molecular descriptors that significantly contribute to the three key neuropharmacokinetic properties related to BBB drug transport (<i>K</i>_p,uu,brain), intracellular accumulation (<i>K</i>_p,uu,cell), and binding and distribution in the brain (<i>V</i>_u,brain) for a set of 40 compounds were identified using partial least-squares (PLS) analysis. The tailoring of drug properties for improved brain exposure includes decreasing the polarity and/or hydrogen bonding capacity. The design of CNS drug candidates with intracellular targets may benefit from an increase in basicity and/or the number of hydrogen bond donors. Applying this knowledge in drug discovery chemistry programs will allow designing compounds with more desirable CNS pharmacokinetic properties