Computational drug design targeting MYH7 for hypertrophic cardiomyopathy integrating molecular docking, Density Functional Theory, and Molecular Dynamics Simulations

Hypertrophic cardiomyopathy (HCM) is a genetic condition of the heart that is commonly associated with mutations of sarcomeric proteins such as MYH7. Currently available therapies are largely palliative and do not offer cure-focused treatment. In this work, we utilize a computational approach combining molecular docking, Density Functional Theory (DFT), and Molecular Dynamics (MD) simulations to search for therapeutic compounds interacting with the MYH7 protein. Predicted models of MYH7 by Alpha Fold provided strong prediction reliability since 91.4% of residues were in the favored Ramachandran region. Out of multiple bioactive candidates screened, thymoquinone showed the most negative free energy of binding (-6.7 kcal/mol) to MYH7. Pharmacophore modeling along with ADMET analysis also validated its druglike nature and declared safety. Analyzing electronic properties showed that thymoquinone possesses a low HOMO-LUMO band gap (~5.67 eV), thus showcasing strong bioreactivity and stability. These results provide a direction for the intervention of MYH7 protein dysfunction. Such progress would aim at changing the treatments from palliative strategies to curative approach which is particularly essential to mitigate the risk of sudden cardiac death, especially in children. However further in vitro and in vivo studies are required to validate the safety and efficiency of the thymoquinone.