Reducing Off-Target Activity of CPP-115 by Targeting Conformational Flexibility of a Reactive Intermediate
Year: 2025
Type: preprint
Abstract: Mechanism-based inhibitors (MBIs) of γ-aminobutyric acid aminotransferase (GABA-AT) are a major therapeutic option for disorders associated with dysregulated GABA levels. However, off-target activity against ornithine aminotransferase (OAT) remains a major challenge for clinical use of GABA-AT MBIs. In this study, we investigated α-substitution of CPP-115 to modulate the conformational flexibility of its reactive intermediate, a key determinant of OAT-specific inactivation. Metadynamics simulations revealed that ethyl substitution can interrupt the conformational transition of the reactive intermediate. Among synthesized derivatives, ethyl and hydroxymethyl substitutions achieved improved GABA-AT/OAT selectivity from CPP-115, whereas ethynyl enhanced OAT selectivity, thereby a loss of GABA-AT selectivity. These findings demonstrate that targeting conformational flexibility is an effective strategy for enhancing selectivity and also can provide structural information for the rational design of next-generation MBIs for GABA-AT and OAT.
Source: ChemRxiv
Authors: Koon Mook Kang, Richard B. Silverman
Institution: Northwestern University
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4415525231