In silico modeling of 22 MYH7 mutant proteins revealed that Arg719Trp and Arg723Gly mutations enhance mavacamten binding affinity, whereas the Gly741Trp mutation disrupts it.
Does mavacamten binding affinity differ between wild-type and MYH7 mutant proteins associated with hypertrophic cardiomyopathy?
Computational modeling suggests that specific MYH7 mutations alter mavacamten binding affinity, highlighting the potential for genotype-tailored therapies in hypertrophic cardiomyopathy.
Mutations in the MYH7 gene, which encodes β-myosin heavy chain (β-MHC), are a significant cause of hypertrophic cardiomyopathy (HCM). These variants may lead to variable clinical outcomes, thereby influencing responsiveness to targeted therapies such as mavacamten, a cardiac myosin inhibitor. In this study, we employed AlphaFold modeling to construct structural models of both wild-type (WT) and mutant β-MHC associated with HCM. We performed molecular docking to evaluate the binding affinity of mavacamten for 22 MYH7 mutant proteins. A subset of variants was further analyzed using molecular dynamics (MD) simulations and molecular mechanics with Poisson-Boltzmann and surface area (MM/PBSA) binding free energy calculations. Our results provide preliminary evidence that the Arg719Trp and Arg723Gly mutations enhance mavacamten binding, whereas the Gly741Trp mutation disrupts binding affinity. Interestingly, variants such as Arg453Cys and Thr1377Met, although exhibiting increased structural flexibility, maintained favorable interaction profiles. These findings provide insights into how specific mutations affect drug-binding behavior and may inform future efforts toward genotype-tailored treatment strategies for HCM.
Widjaja et al. (Tue,) conducted a other in Hypertrophic cardiomyopathy (HCM). Mavacamten vs. Wild-type (WT) β-MHC was evaluated on Binding affinity of mavacamten. In silico modeling of 22 MYH7 mutant proteins revealed that Arg719Trp and Arg723Gly mutations enhance mavacamten binding affinity, whereas the Gly741Trp mutation disrupts it.