Table 2.

Mode of direct interaction of curcumin and curcumin analogues with various biomolecules^a

Molecule	Finding
Inflammatory molecules
TNF-α	Interacted with TNF-α by hydrophobic, van der Waals forces, and H-bond. Cys129 in TNF-α was found as the binding site for curcumin.31
COX-1	Inhibited the enzyme activity by direct binding through Ser530.34
COX-2	Inhibited the enzyme activity by direct binding through Val523, Val116, Ala516 and Tyr355;34 interacted by hydrogen bonds with Ala562 and inhibited PGE-2 production.35
	b Interacted by forming hydrogen bonds with Glu346, Phe580, Asn101, and Gln350 and inhibited PGE-2 production.35
AGP	Binds at two sites on the outer region of AGP, the open end of the central hydrophobic cavity and on a surface cleft.40
MD-2	Inhibited LPS signaling by binding to the Cys133 residue inside a hydrophobic pocket of MD-2 through Michael addition reaction.41
Enzymes
HAT (p300/CBP)	Formed a covalent association with p300, promoted proteasome-dependent degradation of p300, and inhibited acetyltransferase activity.21
HDAC	Made several close contacts with the active site residues of enzyme and exhibited potent HDAC inhibitory activity.42
GLOI	Inhibited enzyme activity (Ki, 2.6–4.6 μM), coordinated with Zn2+ in the active site of GLOI through oxygen atoms of carbonyl group;44 the keto and enol forms interacted through hydrophobic interactions with binding free energies of −24.16 and −30.38 kcal mol−1, respectively.45
XO	Degradation product of curcumin exhibited effective inhibitory activity in comparison to curcumin; the binding pocket for interaction consisted of Phe914, Phe1009, and Thr1010 on XO.49
Proteasome	Inhibited proteasome activity by direct binding to the amino-terminal threonine (Thr1) of the β5 CT-like subunit of the proteasome.50
	*Exhibited potent anti-proliferative and proteasome inhibition activity by direct binding to the β5 subunit.51
SERCA	Stabilized the E1 conformation of SERCA, bind to a site that induced conformational changes and precluded ATP from binding to SERCA-Ca2+ pump.52
SERCA2	Induced ER stress and inhibited survival of human liposarcoma cells, co-localized with SERCA2 in ER and inhibited the enzyme activity by direct interaction with Asp254, Arg264, and Gln56 residues.53
PfATP6	Exhibited anti-malarial effects by binding directly to the PfATP6 through hydrophobic interactions and hydrogen bonds.55
HIV-1 IN	Bind directly to the active site of enzymes, o-hydroxyl and/or keto–enol structures were important for IN inhibitory actions;56 interacted with integrase catalytic core.57
HIV-1 PR	Bind directly to the active site of enzymes, o-hydroxyl and/or keto–enol structures were important for PR inhibitory actions.56
DNMT1	Exerted inhibitory effect by covalently blocking catalytic Cys1226 of DNMT1.59
DNA Pol λb	Bind selectively to the N-terminal domain, binding site consisted of β-sheet (Thr51 of sheet-1), the α-helix (residues 57–69) and the two loops (residues 51–56 and 70–75).60
RNase Ab	Bind to the RNase with binding constant of 104 M−1. The oxygen atoms at positions 3 and 5 of DAC formed a hydrogen bond with Tyr97, Gln11 and Lys7 of RNase.61
Lipoxygenase	Inhibit soybean lipoxygenase L3 activity by blocking the active site,63 binds in a non-competitive manner and undergoes photodegradation in the crystallographic X-rays.64
P-12-LOX	Binds to the enzyme, inhibited enzyme activity, and reduced sprout formation in an in vitro model of angiogenesis.65
MMPsb	Interaction was formed by three hydrogen bonds and was associated with a docking energy of −11.46 kcal mol−1.70
Lysozyme	Binds to lysozyme with a binding constant of 1.2 × 103 M−1.73
HEWL	Exhibited inhibitory activity against the fibrillation of hen lysozyme, showed interaction predominantly by van der Waals force or by hydrogen bonding.74
Protein kinases
PKC	Binds to the C1B subdomains of PKC by forming hydrogen bonds with the residues at the activator binding site of enzyme (EC50, 4–11 μM).78
Src	Inhibited v-Src kinase activity, decreased tyrosyl substrate phosphorylation of Shc, cortactin, FAK, and reduced proliferation of v-Src transformed cells.80
GSK-3β	Inhibited the activity by direct binding to the Val135, Ile62, Arg141, and Lys85 concomitant with an increase in liver glycogen reserves in fasting BALB/c mice.89
ErbB2	Increased association of CHIP with ErbB2, induced ubiquitination and depletion of ErbB2 by binding to the kinase domain.91
PhK	Inhibited enzyme activity selectively in a non-competitive manner (Ki, 75 μM).93
Protein reductases
TrxR	Inhibited activity by inducing alkylation of Cys496/Sec497 in the catalytically active site of the enzyme;20 at least one methoxy group in curcumin is necessary for interaction with TrxR.95
ALR2	Inhibited activity in a non-competitive manner (IC50, 10 μM), interacted with Tyr48, Lys21, Thr19, Gln183, Leu300 and Trp111 of ALR2.97
AKR1B10b	Exhibited selectivity and potency by interacting with Trp21, Gln114, Trp220, Val301 and Ser304 residues.100
Carrier proteins
CMs	Formed a complex with CMs (CM-curcumin) through hydrophobic interactions, the IC50 of CM-curcumin complex was reduced from 14.85 to 12.69 μM.110
αS1-casein	Binds to the αS1-casein at two binding sites, one with high affinity (2.01 × 106 M−1) and the other with low affinity (6.3 × 104 M−1) predominantly by hydrophobic interactions.111
HSA	Exhibited strong association with the hydrophobic domains of HSA, interaction suppressed curcumin degradation due to hydrolysis.118
	b Interacted through hydrophobic forces with Arg218, Asn295, and Tyr452 of HSA.119
BSA	Binds via hydrophilic and hydrophobic interactions with a binding constant of 3.33 ± 0.8 × 104 M−1.120
	b Enol form docked to hydrophobic subdomain preferentially near Trp213 of BSA.121
Fibrinogen	Exhibited strong association with the hydrophobic domains of fibrinogen, interaction suppressed curcumin degradation due to hydrolysis.118
βLG	Interacted through hydrophobic contacts, encapsulation of curcumin in βLG nanoparticles enhanced the solubility and stability of curcumin;123 interacted through phenolic hydroxyl group, two tryptophan residues (Trp19 and Trp61) in β-LG were critical for interaction.124
Ig	Interacted with an average affinity constant of 1.170 × 104 predominantly through hydrogen bonds and hydrophobic forces.126
Others
Bcl-2	Interacted directly with cavity 2 through multiple amino acids, abrogated Bcl-2 activity and enhanced apoptosis.129
FtsZ	Inhibited the assembly of FtsZ protofilaments and bacterial cytokinesis and increased the GTPase activity of FtsZ;135 interacted with the active site ‘pocket 1’ of FtsZ by hydrogen bonds.136
PrP	Binds selectively to the non-native β-forms and α-helical intermediate of PrP.138
DNA	Binds to the major and minor grooves of DNA duplex with overall binding constants of 4.255 × 104 M−1.16
	b Interacted with the minor groove of ct-DNA, the binding site was 3 base pairs long and involved AT residues.15
RNA	Binds to the RNA bases and also to the backbone phosphate group with overall binding constants of 1.262 × 104 M−1.16
TTR	Binds to the active site of TTR with a molar ratio of 1.2 : 1 and with a Kd of 2.3 × 10−6 M, stabilizes the TTR by preventing denaturant induced tertiary and quaternary structural changes.140
Ca2+/CaMb	Antagonizes Ca2+/CaM functions by binding directly to the C-terminal hydrophobic pocket of enzyme and inhibited the cell cycle progression of colon cancer cells.141
Tubulin	Inhibited proliferation of HeLa and MCF-7 cells, inhibited tubulin assembly into microtubules by direct binding, reduced GTPase activity and induced aggregation of tubulin dimers.142
CD13/APN	Inhibited APN activity irreversibly by direct binding that was concomitant with its ability to inhibit invasion of APN-positive tumor cells.143
Abeta	Enol form of curcumin exhibited strong binding.144,145
Glutathione	Formed mono- and di-glutathionyl-adducts of curcumin; presence of GSTP1-1 significantly accelerated the initial rate of GSH- mediated consumption of curcumin.148
Keap1	Disrupts the Nrf2-Keap1 complex by interaction with the thiol group of Keap1 through a Michael addition reaction.151
Metals
Cu2+, Fe2+, Zn2+	Exerted anti-AD effects by preventing amyloid aggregation and inducing Cu2+, Fe2+, and Zn2+ chelation.19

^aAbeta, β-amyloid; AD, Alzheimer’s disease; AGP, α1-acid glycoprotein; Ala, alanine; ALR, aldose reductase; APN, aminopeptidase N; Arg, arginine; Asn, asparagines; Asp, aspartic acid; Bcl-2, B-cell lymphoma-2; BSA, bovine serum albumin; Ca²⁺/CaM, Ca²⁺/calmodulin; CBP, CREB-binding protein; CHIP, carboxyl terminus of Hsc70-interacting protein; CMs, casein micelles; COX, cyclooxygenase; ct, calf thymus; CT, chymotrypsin; Cys, cysteine; DNMT, DNA methyltransferase; ER, endoplasmic reticulum; FAK, focal adhesion kinase; Gln, glutamine; GLOI, glyoxalase I; Glu, glutamic acid; GSK-3β, glycogen synthase kinase-3β; GST, glutathione S-transferase; GTPase, guanosine triphosphatase; HAT, histone acetylase; HDAC, histone deacetylase; HEWL, hen egg-white lysozyme; HIV-1 IN, human immunodeficiency virus type 1 integrase; HIV-1 PR, human immunodeficiency virus type 1 protease; HSA, human serum albumin; Ile, isoleucine; Ig, immunoglobulin; Keap1, Kelch-like ECH-associated protein 1; K_d, dissociation constant; Ki, inhibition constant; Leu, leucine; LPS, lipopolysaccharide; Lys, lysine; MD-2, myeloid differentiation protein-2; MMPs, matrix metalloproteinases; P-12-LOX, platelet 12-lipoxygenase; PGE, prostaglandin; Phe, phenylalanine; PhK, phosphorylase kinase; PKC, protein kinase C; Pol λ, polymerase λ; PrP, prion protein; RNase, ribonuclease; Sec, selenocysteine; Ser, serine; SERCA, sarco (endo) plasmic reticulum Ca²⁺-ATPase; Shc, src homology/collagen protein; Thr, threonine; TNF-α, tumor necrosis factor-α; Trp, tryptophan; TrxR, thioredoxin reductase; TTR, transthyretin; Tyr, tyrosine; Val, valine; Src, sarcoma; XO, xanthine oxidase; βLG, β-lactoglobulin.

^bThese targets interact directly with the curcumin analogues.