Advances in computational methods for PROTAC drug discovery
Massyel S. Martínez-Cortésa, Carlos A. Velázquez‐Martínezb✉, José L. Medina‐Francoc✉
- aDIFACQUIM Research Group, Department of Pharmacy, School of Chemistry, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
- bFaculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada. Electronic address: velazque@ualberta.ca
- cDIFACQUIM Research Group, Department of Pharmacy, School of Chemistry, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico. Electronic address: medinajl@unam.mx
- ✉Corresponding author
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Abstract
Proteolysis-targeting chimeras (PROTACs) represent a transformative strategy in drug discovery, enabling the selective degradation of target proteins rather than merely inhibiting their activity. However, their structural complexity and deviation from conventional drug-like properties present major challenges for traditional design and optimization methods. In this review, we provide a comprehensive overview of recent computational advances that facilitate PROTAC development, encompassing chemoinformatics, structural bioinformatics, molecular modeling and machine learning resources. We highlight computational tools for warhead and linker design, ternary complex modeling and the prediction of degradation efficiency and ADMET profiles. Finally, we discuss current limitations and future perspectives, emphasizing strategies to enhance design effectiveness and accelerate clinical translation.
TL;DRA comprehensive overview of recent computational advances that facilitate PROTAC development is provided, encompassing chemoinformatics, structural bioinformatics, molecular modeling and machine learning resources. (Semantic Scholar)