Key result
Cryo-EM revealed that GDC-0310 engages NaV1.7-VSD4 through an unexpected binding mode orthogonal to arylsulfonamides, identifying a previously unknown ligand binding site.
Why the study?
Current NaV channel blockers lack subtype selectivity, and known NaV1.7-selective inhibitor classes have undesirable characteristics, while structural understanding of acylsulfonamide inhibitors has been limited.
Cryo-EM reveals a novel binding site for NaV1.7 inhibitors, enabling the rational design of potent hybrid inhibitors for pain management.
Novel NaV1.7 site may guide hybrid inhibitor design; hypothesis-generating for pain, requires human validation.
The voltage-gated sodium (Na V ) channel Na V 1.7 has been identified as a potential novel analgesic target due to its involvement in human pain syndromes. However, clinically available Na V channel-blocking drugs are not selective among the nine Na V channel subtypes, Na V 1.1–Na V 1.9. Moreover, the two currently known classes of Na V 1.7 subtype-selective inhibitors (aryl- and acylsulfonamides) have undesirable characteristics that may limit their development. To this point understanding of the structure–activity relationships of the acylsulfonamide class of Na V 1.7 inhibitors, exemplified by the clinical development candidate GDC-0310 , has been based solely on a single co-crystal structure of an arylsulfonamide inhibitor bound to voltage-sensing domain 4 (VSD4). To advance inhibitor design targeting the Na V 1.7 channel, we pursued high-resolution ligand-bound Na V 1.7-VSD4 structures using cryogenic electron microscopy (cryo-EM). Here, we report that GDC-0310 engages the Na V 1.7-VSD4 through an unexpected binding mode orthogonal to the arylsulfonamide inhibitor class binding pose, which identifies a previously unknown ligand binding site in Na V channels. This finding enabled the design of a novel hybrid inhibitor series that bridges the aryl- and acylsulfonamide binding pockets and allows for the generation of molecules with substantially differentiated structures and properties. Overall, our study highlights the power of cryo-EM methods to pursue challenging drug targets using iterative and high-resolution structure-guided inhibitor design. This work also underscores an important role of the membrane bilayer in the optimization of selective Na V channel modulators targeting VSD4.
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Kschonsak et al. (2023) studied this question. GDC-0310 was evaluated on Binding mode of GDC-0310 to NaV1.7-VSD4. Cryo-EM revealed that GDC-0310 engages NaV1.7-VSD4 through an unexpected binding mode orthogonal to arylsulfonamides, identifying a previously unknown ligand binding site.
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