3rd International Conference on Chemo and BioInformatics, Kragujevac, September 25-26. 2025. (pp. 648-651)
АУТОР(И) / AUTHOR(S): Milan Mladenović, Nevena Tomašević, Gordana Tasić, Predrag Jovanović, Milena Simić, Vladimir Savić, Sanja Lj. Matić
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DOI: 10.46793/ICCBIKG25.648M
САЖЕТАК / ABSTRACT:
Developing HDAC4-targeting PROTACs could offer a cost-effective strategy for SMA palliation by promoting selective HDAC4 degradation, reducing atrogin-1 and MuRF1 upregulation, and thereby slowing muscle protein loss and atrophy progression. The design of HDAC4-targeting PROTACs in this study relied on the irreversible structure-based alignment of co-crystallized HDAC4 inhibitors (HDAC4Is) to identify optimal zinc-binding groups, which were then used as anchoring moieties for autonomous fragment-based PROTAC construction with linkers and VHL-1 or CRBN ligands, using the in-house Py_AutoPROTAC_Designer workflow. Modeled HDAC4:PROTAC:E3 ligase ternary complexes revealed, by applying a rank- by-rank strategy, high-affinity and synthetically tractable candidates, exhibiting predicted potencies in the picomolar range, ready to be promptly synthesized and submitted to enzymatic assays, cellular (in vitro) models, and animal (in vivo) studies.
КЉУЧНЕ РЕЧИ / KEYWORDS:
SMA, HDAC4, PROTACs, covalent docking, autonomous design
ПРОЈЕКАТ / ACKNOWLEDGEMENT:
This research was supported by the Science Found of the Repablic of Serbia, #GRANT No 7490, Artificial Intelligence-Guided Design, Synthesis, and Pharmacological Evaluation of Innovative PROTACs as Degraders of HDAC4, an Epigenetic Target for Spinal Muscular Atrophy – SMAIPROTACs and by the Ministry of Science, Technological Development and Innovation, Republic of Serbia, Grants: No. 451-03-136/2025-03/ 200378, No 451-03-137/2025-03/ 200122, No 451-03-136/2025-03/ 200161, and No 451-03-137/2025-03/ 200161.
ЛИТЕРАТУРА / REFERENCES:
- N. Tomašević, Histone deacetylase 4 (HDAC4), an epigenetic target for spinal muscular atrophy, Biologica Serbica, 45 (2023) 52-64.