Inverted binding due to a minor structural change in berberine enhances its phospholipase A2 inhibitory effect

Chandra, Dhanesh; Abhilash, Joseph; Prasanth, Ganesh K.; Sabu, Abdulhameed; Sadasivan, C.; Haridas, M.

doi:10.1016/j.ijbiomac.2012.01.029

Cited by 11 publications

(1 citation statement)

References 23 publications

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“…The clinical efficacy of berberine is mediated by interacting with a mixture of biological pathways, which are involved in metabolism ( Moghaddam et al, 2014 ; Zhang et al, 2014 ), transmission of signals ( Chen et al, 2017 ; Spatuzza et al, 2014 ; Yue et al, 2017 ) and regulation of gene expression ( Bhadra and Kumar, 2011 ). Increasing evidences indicate that berberine can act on a diverse range of molecular targets by binding to the active cavities that are to have certain structural and physiochemical properties, such as QacR ( Schumacher et al, 2001 ), BmrR ( Newberry et al, 2008 ), RamR ( Yamasaki et al, 2013 ), phospholipase A 2 (PLA 2 ) ( Chandra et al, 2012 ) and double helix DNA d(CGTACG) 2 ( Ferraroni et al, 2011 ). According to the co-crystal structures of these targets in complex with berberine, berberine binds highly site-specifically by interacting with residues flanking a hydrophobic groove in the pocket.…”

Section: Introductionmentioning

confidence: 99%

Polypharmacology of Berberine Based on Multi-Target Binding Motifs

et al. 2018

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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-β1-42 (Aβ1-42). Further study indicated that berberine acted as a high-affinity BACE1 inhibitor and prevented Aβ1-42 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.

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