Fig. 9
Virtual screening of FDA-approved drug libraires identifies several promising drug candidates for treatment of R2834H-induced cardiocutaneous diseases. (a) Rationale of drug-repurposing strategy based on the use of bulky FDA-approved compounds with high affinity towards mutant DP CT tail to maintain it in a neutral position (binding neither PLEC14 nor PLEC17) through the masking of positively charged arginine residues and the known GSK3 phosphorylation site Ser2949. (b) Pipeline detailing the workflow of the virtual screening (VS) and the different filters used to narrow down the number of drug candidates from 5317 to the 3 best compounds. (c) Several examples of molecular docking illustrating the different types of Ser2849 masking obtained during VS. Only drugs masking at least partially Ser2849 were selected. Grey: R2834H DP CT tail (PEP-FOLD). Red: Ser2849. Green: FDA-approved compound (PubChem, NIH). (d) Heat map displaying the top 60 candidates sorted by binding affinity (kcal/mol, left column) towards mutant DP CT tail. Other parameters include: remaining SASA of arginines (Å2), Ser2849 masking (%) and molecular weight (g/mol). SASA calculated using EDTSurf algorithm, (iCn3D, NIH). For each parameter, the best values are highlighted in blue, the worst values in red. Each drug can be identified through his CID number (PubChem, NIH) (left) and brand name (right). Note that a same compound can appear several times due to different docking positions. (e) Arginine-masking properties of top 60 candidates. (f) Top 13 candidates that are the most capable of masking arginine residues in mutant DP CT tail (remaining arginine SASA < 900 Å2). (g) Ser2849-masking properties of top 60 candidates. (h) Top 14 candidates that are the most capable of masking Ser2849 in mutant DP CT tail (masking > 90%). (i-n) 2D scatter plots comparing two distinct parameters at a time namely: binding affinity (kcal/mol), remaining SASA of arginines (Å2), Ser2849 masking (%) and molecular weight (g/mol). The best candidates are located in the dark blue zone with respective labels. (o) Number of hits referring to the number of times a same compound appears in the output of VS (number of docking positions). (p) Key examples of top 3 FDA-approved drug candidates in docking positions on mutant R2834H DP CT tail. Respective abilities in Ser2849 masking and arginine masking are indicated. Grey: R2834H DP CT tail (PEPFOLD). Red: Ser2849. Green: FDA-approved compound (PubChem, NIH). DelPhi surface with potential in the last row obtained from iCn3D (NIH) with following settings: potential contour set at 2kT/e (25.6mV at 298 K) with salt concentration at 0.15 M.
