Muricins as Potential Natural B-cell Lymphoma-extra-large (Bcl-xL) Inhibitors: A Multiscale in Silico Approach Targeting Apoptosis and Chemoresistance in Cancer
DOI:
https://doi.org/10.11113/mjfas.v22n3.4885Keywords:
Muricin H, Muricin I, Molecular docking, Molecular dynamics, Network pharmacology.Abstract
Resistance to apoptosis mediated by overexpression of anti-apoptotic proteins such as B-cell lymphoma-extra-large (Bcl-xL) is notable in most cancers. Natural acetogenins, including muricin I and muricin H from Annona species, are structurally unique compounds with cytotoxic potential, yet their mechanisms of action in ovarian cancer remain unexplored. This study integrates molecular docking, ADMET profiling, network pharmacology, and molecular dynamics (MD) simulations to investigate the potential of muricin I and H as Bcl-xL inhibitors. Molecular docking revealed strong binding affinities of muricin I/Bcl-xL and muricin H/Bcl-xL complexes with binding energies of –11.9 kcal/mol and –11.6 kcal/mol, respectively, suggesting potential inhibitory activity. ADMET analysis showed favourable pharmacokinetic profiles, including good oral bioavailability and low predicted toxicity (class IV). To further contextualize these findings, network pharmacology was employed to identify overlapping targets with ovarian cancer and apoptosis-related genes. Enrichment and protein–protein interaction analyses highlighted Bcl-xL and related apoptosis pathways as central nodes along with chemoresistance signalling, with key hub genes such as BCL2 and CASP3 linking to platinum resistance pathways. These findings reflect the polypharmacological nature of muricin compounds and suggest potential synergistic effects relevant to tumour progression. Finally, 100 ns of MD simulations confirmed the structural stability of muricins/Bcl-xL complexes, with consistent RMSD values of 1.29 ± 0.23 Å (muricin I) and 1.31 ± 0.16 Å (muricin H), supporting strong and stable binding interactions. This is the first study to identify muricin I and muricin H as Bcl-xL inhibitors, highlighting their potential as natural multi-target pro-apoptotic agents.
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