Work

QSAR and Free–Wilson Analysis of Bioisosteric Derivatives of Dimebon to Optimize the Search for Potential Inhibitors of Mitochondrial Permeability Transition

Year: 2026

Type: article

Abstract: Mitochondrial permeability transition pore (MPTp) opening is a critical event in neurodegeneration, representing a point of no return in cell death cascades. Despite the neuroprotective potential of MPTp inhibitors, systematic structure-activity relationship (SAR) studies for this target remain scarce. Here we present the first standardized dataset of 57 γ-carboline derivatives evaluated for their ability to inhibit MPTp under uniform experimental conditions. Using complementary Free-Wilson and 2D-QSAR analyses, we expertly propose rational structure-activity relationships (SAR) for this scaffold. Based on the Free-Wilson analysis, we assume that increasing lipophilicity and steric bulk at all four substitution positions to a certain limit positively correlates with inhibitory activity. The R3 linker plays a critical role: the presence of positively ionizable amine groups and potentially hydrogen bond donors enhances activity, whereas non-ionizable amide linkers may be detrimental. The QSAR model based on physicochemical descriptors of substituents corroborates these findings, with positive contributions from cLogP and HBD descriptors. This integrated computational-experimental approach provides a predictive framework for the rational design of novel neuroprotective agents targeting MPTp, with potential implications for the treatment of neurodegenerative diseases.

Source: Molecules

DOI: 10.3390/molecules31203775