Binding patterns and structural dynamics of Brucea javanica bioactives as anti-diabetic leads: integrative insights from network-based analysis, fragment molecular orbital, and molecular dynamics simulations

Abstract

This study investigated the therapeutic potential of <i>Brucea javanica</i> bioactive compounds as antidiabetic agents through an integrated network pharmacology and molecular interaction analysis approach. Network-based analysis identified three key protein targets, including peroxisome proliferator-activated receptor gamma (PPARG), matrix metalloproteinase 2 (MMP2), and insulin-like growth factor 1 receptor (IGF1R), which are closely linked to glucose regulation. Molecular docking revealed favourable binding conformations of Yadanziolide A, Mecadonic acid, Isofouquierone peroxide, and Javanicin with these targets, with the strongest binding affinity observed for PPARG. To gain deeper insights, pairwise interaction energies (PIE) were calculated within a 10 Å radius of the PPARG binding pocket using the FMO-RIMP2/PCM method. Two ligand–protein complexes, Yadanziolide A and Isofouquierone peroxide exhibited higher PIE values compared to the reference compound and were further subjected to MD simulations. Model 1 displayed greater structural stability than Model 2, as confirmed by binding energy profiles and dynamic fluctuations. Pair interaction energy decomposition analysis of Model 1 indicated that interactions of Yadanziolide A with GLU343, ILE263, and PHE264 were primarily governed by electrostatic forces, underscoring their critical contribution to complex stabilisation. These findings provide molecular insights into the antidiabetic potential of <i>B. javanica</i> bioactives.

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