Comprehensive DFT Exploration of the Electronic Structure, Aromaticity, and Non-Covalent Interaction Landscape of Mavacamten

Abstract

In this study, the molecular architecture and electronic properties of mavacamten—a selective cardiac myosin inhibitor used in the treatment of obstructive hypertrophic cardiomyopathy—were examined through a detailed density functional theory (DFT) investigation. Geometry optimization and electronic-structure calculations were performed using the B3LYP functional with the 6-311G(d,p) basis set. Mulliken charge analysis identified electron-rich and electron-deficient regions that govern the molecule’s reactivity, while non-covalent interaction (NCI) mapping revealed the presence of steric congestion, van der Waals contacts, and weak hydrogen-bond features. Simulated scanning tunneling microscopy (STM) images provided insight into the spatial distribution of the local density of states, highlighting enhanced electronic activity around heteroatom sites. Aromaticity indices—including FLU, PDI, HOMA, BIRD, and PLR—confirmed a highly delocalized and structurally stable aromatic core. Further investigation of Laplacian electron density and Mayer bond orders clarified the balance between strongly conjugated carbon–carbon bonds and weak peripheral interactions. The Core–Valence Bifurcation (CVB) index indicated the predominance of weak hydrogen-bond interactions within the structure. Collectively, these computational findings deliver a comprehensive depiction of mavacamten’s electronic landscape and bonding characteristics, providing a theoretical foundation for future structural modifications and mechanistic studies.