Polypharmacology of Berberine Based on Multi-Target Binding Motifs.

Background: Polypharmacology is emerging as the next paradigm in drug discovery. However, considerable challenges still exist for polypharmacology modeling. In this study, we developed a rational design to identify highly potential targets (HPTs) for polypharmacological drugs, such as berberine. Methods and Results: All the proven co-crystal structures locate berberine in the active cavities of a redundancy of aromatic, aliphatic, and acidic residues. The side chains from residues provide hydrophobic and electronic interactions to aid in neutralization for the positive charge of berberine. Accordingly, we generated multi-target binding motifs (MBM) for berberine, and established a new mathematical model to identify HPTs based on MBM. Remarkably, the berberine MBM was embodied in 13 HPTs, including beta-secretase 1 (BACE1) and amyloid-ß1-42 (Aß1-42). Further study indicated that berberine acted as a high-affinity BACE1 inhibitor and prevented Aß1-42 aggregation to delay the pathological process of Alzheimer's disease. Conclusion: Here, we proposed a MBM-based drug-target space model to analyze the underlying mechanism of multi-target drugs against polypharmacological profiles, and demonstrated the role of berberine in Alzheimer's disease. This approach can be useful in derivation of rules, which will illuminate our understanding of drug action in diseases.

Staphylococcus aureus Phenol-Soluble Modulins α1-α3 Act as Novel Toll-Like Receptor (TLR) 4 Antagonists to Inhibit HMGB1/TLR4/NF-κB Signaling Pathway.

Phenol-soluble modulins (PSMs) have recently emerged as key virulence determinants, particularly in highly aggressive Staphylococcus aureus isolates. These peptides contribute to the pathogenesis of S. aureus infections, participating in multiple inflammatory responses. Here, we report a new role for S. aureus PSMs in high mobility group box-1 protein (HMGB1) induced inflammation by modulating toll-like receptor (TLR) 4 pathway. Direct ligation of TLR4 with S. aureus PSMα1-α3 and PSMß1-ß2 was identified by surface plasmon resonance. Remarkably, the binding affinity of TLR4 with HMGB1 was attenuated by PSMα1-α3. Further study revealed that PSMα1-α3 directly inhibited HMGB1-induced NF-κB activation and proinflammatory cytokines production in vitro using HEK-Blue hTLR4 cells and THP-1 cells. To analyze the molecular interactions between PSMs and TLR4, blast similarity search was performed and identified that PSMα1 and PSMß2 were ideal templates for homology modeling. The three-dimensional structures of PSMα2, PSMα4, PSMß1, and δ-toxin were successfully generated with MODELLER, and further refined using CHARMm. PSMs docking into TLR4 were done using ZDOCK, indicating that PSMα1-α3 compete with HMGB1 for interacting with the surrounding residues (336-477) of TLR4 domain. Our study reveals that S. aureus PSMα1-α3 can act as novel TLR4 antagonists, which account at least in part for the staphylococcal immune evasion. Modulation of this process will lead to new therapeutic strategies against S. aureus infections.