Combining Ligand- and Structure-Based Approaches to Develop Haloacetamide-Derived Di(hetero)arylmethanes as Potential Anticancer Agents
- 1Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Arbuzova Str. 8, Kazan 420088, Russia
- 2Kazan National Research Technological University, K. Marksa Str. 68, Kazan 420015, Russia
- 3A.N. Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences, Vavilova Str., 28, Moscow 119334, Russia
Abstract
The convergence of ligand-based and structure-based computational strategies provides a robust foundation for hit optimization in anticancer drug discovery. We integrated ligand-based SAR with structure-based covalent docking to guide the optimization of haloacetamide-derived di(hetero)arylmethanes. SAR revealed that the 2-haloacetamide warhead is essential, while the di(hetero)aryl scaffold modulates activity, leading to submicromolar bis(pyrazolyl)methane hits. Rather than seeking to establish a definitive molecular target, we used GAPDH and GSTO1 as experimentally motivated target hypotheses to derive structural constraints for covalent scaffold design. Covalent docking was used to prioritize these hypotheses and guide the design of phosphorylated diarylmethane derivatives, leading to the identification of highly cytotoxic bromoacetamide compound, comparable to doxorubicin. In PANC-1 cells, this lead decreased LDH activity and increased PDH activity, suggesting a shift in cellular metabolism from glycolysis toward oxidative phosphorylation. The results demonstrate the utility of target-hypothesis-guided design under conditions in which molecular target identity remains unresolved.
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BibTeX
@article{shibaeva2026combining,
title = {{Combining Ligand- and Structure-Based Approaches to Develop Haloacetamide-Derived Di(hetero)arylmethanes as Potential Anticancer Agents}},
author = {Karina O. Shibaeva and Andrey V. Smolobochkin and Elena A. Chugunova and Hoang Bao Tran Nguyen and Adel M. Shakirov and Elmira M. Gibadullina and Anna P. Lyubina and Anastasiia S. Sapunova and Alexandra D. Voloshina and Yulia R. Aleksandrova and Margarita E. Neganova and Almir S. Gazizov and Alexander R. Burilov and Michail A. Pudovik and Oleg G. Sinyashin},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219559},
url = {https://www.mdpi.com/1422-0067/27/21/9559},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Combining Ligand- and Structure-Based Approaches to Develop Haloacetamide-Derived Di(hetero)arylmethanes as Potential Anticancer Agents
AU - Karina O. Shibaeva
AU - Andrey V. Smolobochkin
AU - Elena A. Chugunova
AU - Hoang Bao Tran Nguyen
AU - Adel M. Shakirov
AU - Elmira M. Gibadullina
AU - Anna P. Lyubina
AU - Anastasiia S. Sapunova
AU - Alexandra D. Voloshina
AU - Yulia R. Aleksandrova
AU - Margarita E. Neganova
AU - Almir S. Gazizov
AU - Alexander R. Burilov
AU - Michail A. Pudovik
AU - Oleg G. Sinyashin
PY - 2026
DA - 2026/10/26
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219559
UR - https://www.mdpi.com/1422-0067/27/21/9559
AB - The convergence of ligand-based and structure-based computational strategies provides a robust foundation for hit optimization in anticancer drug discovery. We integrated ligand-based SAR with structure-based covalent docking to guide the optimization of haloacetamide-derived di(hetero)arylmethanes. SAR revealed that the 2-haloacetamide warhead is essential, while the di(hetero)aryl scaffold modulates activity, leading to submicromolar bis(pyrazolyl)methane hits. Rather than seeking to establish a definitive molecular target, we used GAPDH and GSTO1 as experimentally motivated target hypotheses to derive structural constraints for covalent scaffold design. Covalent docking was used to prioritize these hypotheses and guide the design of phosphorylated diarylmethane derivatives, leading to the identification of highly cytotoxic bromoacetamide compound, comparable to doxorubicin. In PANC-1 cells, this lead decreased LDH activity and increased PDH activity, suggesting a shift in cellular metabolism from glycolysis toward oxidative phosphorylation. The results demonstrate the utility of target-hypothesis-guided design under conditions in which molecular target identity remains unresolved.
SN - 1422-0067
ER -