Application of molecular modeling in predicting palliative features of HDAC4 PROTACs against Spinal Muscular Atrophy

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.