Structure-Based Discovery of Novel Inhibitors for the R719W Mutant β-Cardiac

Myosin in Hypertrophic Cardiomyopathy

Abstract:
Hypertrophic cardiomyopathy (HCM) is an inherited dysregulation of specific β-cardiac
myosin protein functions that causes the sudden mis regulation of myosin heads and increases
the heart's contractility. It can lead to major cardiac failure and is seen in the majorly adult
generation. The mutations of the β-cardiac myosin protein are also responsible for HCM by
altering molecular interactions and increasing ATPase activity. So, for overcoming this
critical problem of HCM, in this research, we specifically targeted the R719W specific
mutation β-cardiac myosin protein for study, and we identified potent hit compounds as
R719W mutation β-cardiac myosin protein inhibitors using various Computational techniques
available in the SilicoXplore platform generated by the SilicoScientia team. From the
SilicoXplore platform, the modern techniques such as Protein modelling, Similarity search
using SilicoDatabase of natural compounds, Molecular docking using BINA docking, and
Toxicity prediction by Tox-AI tool of SilicoXplore are utilized for discovering novel small
molecules for the prevention and inhibition of myosin protein. The overall research is
smoothly performed and executed by the SilicoXplore Platform. The Molecular dynamics
Simulation and MMGBSA results also showed potent interaction between selected hit
compounds and the myosin protein as stable complexes. The final selected compounds are
potential and promising candidates for further innovation and experimental assessment in the
prevention of hypercontractility of the heart and HCM.