QSAR and Free–Wilson Analysis of Bioisosteric Derivatives of Dimebon to Optimize the Search for Potential Inhibitors of Mitochondrial Permeability Transition
- 1Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences (IPAC RAS), Severny Proezd 1, Chernogolovka 142432, Russia
- 2Department of Medicinal Chemistry and Fine Organic Synthesis, Faculty of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1, Building 3, Moscow 119991, Russia
- 3Department of Pharmacology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of Russian Federation, 8 Trubetskaya St., Moscow 119991, Russia
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.
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BibTeX
@article{veselov2026qsar,
title = {{QSAR and Free–Wilson Analysis of Bioisosteric Derivatives of Dimebon to Optimize the Search for Potential Inhibitors of Mitochondrial Permeability Transition}},
author = {Ivan M. Veselov and Denis V. Zverev and Dmitry A. Shulga and Alexey Yu. Aksinenko and Elena R. Milaeva and Vladimir P. Fisenko and Elena F. Shevtsova and Sergey O. Bachurin},
journal = {Molecules},
year = {2026},
month = oct,
doi = {10.3390/molecules31203775},
url = {https://www.mdpi.com/1420-3049/31/20/3775},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - QSAR and Free–Wilson Analysis of Bioisosteric Derivatives of Dimebon to Optimize the Search for Potential Inhibitors of Mitochondrial Permeability Transition
AU - Ivan M. Veselov
AU - Denis V. Zverev
AU - Dmitry A. Shulga
AU - Alexey Yu. Aksinenko
AU - Elena R. Milaeva
AU - Vladimir P. Fisenko
AU - Elena F. Shevtsova
AU - Sergey O. Bachurin
PY - 2026
DA - 2026/10/01
JO - Molecules
DO - 10.3390/molecules31203775
UR - https://www.mdpi.com/1420-3049/31/20/3775
AB - 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.
SN - 1420-3049
ER -