Figure 6

In-silico identification of sarcomere druggable targets for the resolution of the TNNT2^R92Q/+ phenotype when Mavacamten’s action is suboptimal. (a) Based on identified pathophysiology, the in-silico designed drug should selectively reduce calcium sensitivity of troponin C and shift the steady state relationship between calcium bound to troponin and free calcium to the right. (b,c) Effect of the in-silico designed drug on tension amplitude (b) and relaxation (c) of a simulated TNNT2^R92Q/+ cardiomyocyte. (d,e) Comparison of the effects of 0.5 \(\upmu\)M Mavacamten and the in-silico designed drug (50% calcium desensitisation of the thin filament) on the tension amplitude (d) and relaxation (e) of a population of simulated TNNT2^R92Q/+ cardiomyocytes. Data presented as mean and SD. Significance with respect to untreated control (dotted grey lines) was tested with Kruskal–Wallis with post hoc Dunn correction (N = 348 for each in-silico population). (f) TNNT2^R92Q/+ pressure–volume loop normalisation by the in-silico designed drug. (g–i) Dose-dependent effect of the in-silico designed drug on the LVEF (g), end-diastolic (h), and end-systolic (i) volume of the left ventricle of the virtual TNNT2^R92Q/+ carrier. Yellow areas identify therapeutic windows. The in-silico identified drug restores all phenotype components within therapeutic window.