| dc.description.abstract | Cardiac diseases, such as hypertrophic cardiomyopathy and dilated cardiomyopathy, are characterized by a complex pathophysiology and current medicinal treatments only provide symptomatic relief. A promising pharmacological approach for the treatment of heart diseases is based on small molecules, such as omecamtiv mecarbil and mavacamten, that can directly target and modulate the activity of cardiac myosin II, the key motor protein for muscle contraction. Myosin is a dynamic protein that can adopt various conformations during its functional cycle. Two important conformations are the endpoints of the recovery stroke transition, namely post rigor (PR) and pre-powerstroke (PPS) states. The goal of this research was to develop novel modulators using a rational design approach to identify conformation-selective compounds of human β-cardiac myosin for the tailored treatment of cardiac diseases. New possible target conformations were identified with enhanced Molecular Dynamics (MD) simulations (steered MD and umbrella sampling) of the recovery stroke. Pocket tracking analyses revealed that the binding site is very dynamic with significant changes in physicochemical properties, such as size and polarity. These findings were then used to guide the design of drugs that can selectively stabilise specific myosin structures along the recovery stroke. Several ligands that can preferentially bind different myosin states (PPS, PR and PR- like) were identified using virtual screening, molecular docking, and MD simulations. Hydrogen bond and contact map analyses showed that selectivity towards a specific conformation was related to a higher number of protein-ligand interactions. MD simulations confirmed a stabler binding to the expected state for each ligand. In future, the best candidates can be tested in vitro on single cardiac myosin molecules to measure their effect on myosin force, velocity, and power and determine the type of activity, (activation or inhibition) of each ligand. | en_US |
