Beyond the Veil: Free Energy Profiles and Partition Coefficients for Antimelanoma Drugs in Self-Assembled Nanomicelles via COSMOmic and Atomistic Molecular Dynamics Simulations

This study investigates the encapsulation efficiency (EE) and molecular interactions between amphiphilic dendrimer nanomicelles (AD NMs) and six BRAF inhibitors (BRAFis) used in melanoma treatment: dabrafenib (DAB), vemurafenib (VEM), ponatinib (PON), AZ 628 (AZ), PLX8394 (PLX), and encorafenib (ENC). Experimental determination of EE coupled with computational methods, including molecular dynamics and COSMOmic simulations, was employed to explore the drug encapsulation behavior. The results indicate efficient encapsulation of all BRAF inhibitors by AD NMs with different EE values. DAB, ENC, and PLX exhibit a higher EE (∼75%), while VEM, AZ, and PON show slightly lower encapsulation efficiency (∼60%). Molecular dynamics and COSMOmic simulations identify three binding positions (POS 1, POS 2, POS 3) within the nanocarrier, revealing preferential sites for each BRAFi. Hydrophobic interactions dominate in POS 1, while electrostatic forces play a crucial role in POS 2 and POS 3. Partition coefficient (logK) analysis shows that DAB, ENC, and PLX have higher affinity for the nanocarrier. This study combines experimental and computational insights to improve understanding of BRAFi-AD NM interactions, essential for optimizing drug delivery systems and advancing the development of melanoma treatment.