PMC

Lag time and flux of clebopride across rat skin from Transcutol and isopropyl myristate binary mixtures. Adapted from Rhee ()

3D superposition of: a Diminazene (orange), Nafamostat (yellow) and Hydroxystilbamidine (green) on the catalytic site of Furin; b Apilimod (orange), Pexidartinib (yellow) and Vatalanib (green) on the active site of PIKfyve; c GRL-0617 (orange), Clebopride (yellow) and Mosapride (green) on the S3 and S4 PLpro subsites; d Sofalcone (orange), Bumetanide (yellow) and Stepronin (green) on the Helicase NTPase binding site. Hydrogen bond interaction represented as black dashed lines

Proposed N-dealkylation binding poses of 4-aminopiperines, (A) astemizole, (B) bamipine, (C) benperidol, (D) bezitramide, (E) cisapride, (F) clebopride, (G) domperidone, (H) enzastaurin, (I) fentanyl, (J) indoramin, (K) lorcainide, (L) α-methylfentanyl, (M) pimozide, (N) sabeluzole, and (O) timiperone. Conformation and orientation are generated by AutoDock and selected from one of the lowest energy binding poses and illustrated using PyMOL. Essential active site regions are colored and marked.

Validation of the positive compounds on solid media assays. (a–c) The motor defect phenotype observed in ATXN3-CAG89 worms was significantly rescued when treated with (a) butaclamol (**P < 0.01), or naphazoline, diacerein, chlorpropamide, sulfaphenazole, etodolac, octoclothepin (****P < 0.0001 for all previous compounds); (b) isotretinoin (***P < 0.001), ibuprofen, alfacalcidol, cylclophosphamide, nomifensine, methiothepin, biotin (****P < 0.0001 for all mentioned compounds); (c) benserazide, digitonin, acetamide, cyclobenzaprine, chenodiol, fenbufen, and cycloheptadine (****P < 0.0001 for all previous compounds) (by log-rank (Mantel-Cox) test, N = 90–100 per trial, and N = 270–300 when all trials combined). No rescue of the locomotion defect is observed when the ATXN3-CAG89 worms were treated with phorbol 12-myristate 12-acetate, lamotrigine, or clebopride. The concentration of the compounds was tested at 20 μM as in the liquid culture. This experiment was done 3 times