Identification of Isoliensinine as a Novel CCR5 Inhibitor for the Prevention of Skeletal Muscle Atrophy Through Virtual Screening and Experimental Validation

Age-related skeletal muscle atrophy (sarcopenia) poses a major public health challenge, emphasizing the need for safe and effective interventions. Our previous studies demonstrated that C-C chemokine receptor type 5 (CCR5) is a key therapeutic target for skeletal muscle atrophy, as its activation by C-C motif chemokine ligand 11 (CCL11) promotes the dissociation and degradation of the structural protein α-actin, ultimately contributing to muscle loss. To identify potential CCR5 inhibitors, a database of 7860 natural alkaloids was constructed for pharmacophore-based virtual screening using the CCR5–Maraviroc crystal structure. Screening yielded 789 candidates, and subsequent batch molecular docking analysis identified Isoliensinine (ISO), a lotus seed alkaloid, as a potential CCR5 inhibitor with low binding energy (−10 kcal/mol) and stable hydrogen bonding interactions with Glu283 and Tyr251. Molecular dynamics simulations further confirmed the structural stability of the ISO–CCR5 complex. Molecular dynamics simulations further confirmed the structural stability of the ISO-CCR5 complex. In vitro, ISO dose-dependently inhibited CCL11-induced CCR5 activity (IC50 = 1.314 μM) with low cytotoxicity in C2C12 myotubes, and markedly alleviated CCL11-induced myotube atrophy by suppressing CCR5 activation and the upregulation of the muscle atrophy–related markers MAFbx and MuRF1. These findings provide preliminary evidence for ISO as a potential CCR5-targeting candidate for further investigation in sarcopenia.