Multitargeting by curcumin as revealed by molecular interaction studies

Abstract

Curcumin (diferuloylmethane), the active ingredient in turmeric (Curcuma longa), is a highly pleiotropic molecule with anti-inflammatory, anti-oxidant, chemopreventive, chemosensitization, and radiosensitization activities. The pleiotropic activities attributed to curcumin come from its complex molecular structure and chemistry, as well as its ability to influence multiple signaling molecules. Curcumin has been shown to bind by multiple forces directly to numerous signaling molecules, such as inflammatory molecules, cell survival proteins, protein kinases, protein reductases, histone acetyltransferase, histone deacetylase, glyoxalase I, xanthine oxidase, proteasome, HIV1 integrase, HIV1 protease, sarco (endo) plasmic reticulum Ca2+ ATPase, DNA methyltransferases 1, FtsZ protofilaments, carrier proteins, and metal ions. Curcumin can also bind directly to DNA and RNA. Owing to its β-diketone moiety, curcumin undergoes keto–enol tautomerism that has been reported as a favorable state for direct binding. The functional groups on curcumin found suitable for interaction with other macromolecules include the α, β-unsaturated β-diketone moiety, carbonyl and enolic groups of the β-diketone moiety, methoxy and phenolic hydroxyl groups, and the phenyl rings. Various biophysical tools have been used to monitor direct interaction of curcumin with other proteins, including absorption, fluorescence, Fourier transform infrared (FTIR) and circular dichroism (CD) spectroscopy, surface plasmon resonance, competitive ligand binding, Forster type fluorescence resonance energy transfer (FRET), radiolabeling, site-directed mutagenesis, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), immunoprecipitation, phage display biopanning, electron microscopy, 1-anilino-8-naphthalene-sulfonate (ANS) displacement, and co-localization. Molecular docking, the most commonly employed computational tool for calculating binding affinities and predicting binding sites, has also been used to further characterize curcumin’s binding sites. Furthermore, the ability of curcumin to bind directly to carrier proteins improves its solubility and bioavailability. In this review, we focus on how curcumin directly targets signaling molecules, as well as the different forces that bind the curcumin–protein complex and how this interaction affects the biological properties of proteins. We will also discuss various analogues of curcumin designed to bind selective targets with increased affinity.

Development and Evaluation of an In Vitro Vaginal Model for Assessment of Drug’s Biopharmaceutical Properties: Curcumin

“…The affinity of this phytochemical for macromolecules in SVF (pH4.5) was therefore quantified and profound affinity of curcumin for glycoproteins and albumin was demonstrated (Fig. 3, the results of equilibrium dialysis), with slightly higher affinity for glycoproteins than for albumins as corroborated in other published articles (42). Interactions between curcumin and vaginal mucus could thus additionally reduce curcumin accessibility to systemic circulation via vaginal mucosa.…”

Curcumin suppresses HIF1A synthesis and VEGFA release in pituitary adenomas

“…However, as the basal and HIF1A-independent release of VEGFA was also suppressed by curcumin, it is evident that other mechanisms involved in VEGFA production were also affected. It is known that curcumin has multiple targets and therefore interferes with multiple second messenger systems, intracellular signalling pathways and transcription factors (Kunnumakkara et al 2008, Gupta et al 2011, some of which are involved in the stimulatory action of different growth factors and neuropeptides on VEGFA secretion in pituitary adenomas (Renner et al 2004). For instance, it has been shown that TGF-B-induced VEGFA production, a process that is also critically involved in pituitary tumour development (Renner et al 2002), was significantly blocked by curcumin in human HT-1080 fibrosarcoma cells (Shih & Claffey 2001).…”

Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey

“…Curcumin has also been shown to inactivate TNF-␣ by direct binding. 76 In one study, curcumin docked at the receptor-binding sites of TNF-␣ and exhibited direct interaction by both noncovalent and covalent interactions. 77 Curcumin is currently in clinical trials for all those diseases for which TNF blockers have been approved.…”