Structure Activity Relationship

In modern medicine, the first Curcumin study on human diseases was reported in 1937 by Oppenheimer. Since then Curcumin has been noted in more than 4,000 reports on the wide spectrum of biological activities from antioxidant to anti-inflammatory to anticancer. These effects known as “pleiotropic effects” are highly dependent on ability of the molecule to interact and regulate multiple targets. 

Hence, Curcumin, which has the ability to interact with several molecular targets, represents the term polypharmacology as a classical example that elucidates the concept of “one drug-multiple targets” rather than traditional concept of “one drug-one target”.

Curcumin exhibits its biological activities by direct binding and indirect modulation (upregulation or downregulation) of targets. These biological activities are influenced by its chemical structure—two phenyl groups connected by a methylene bridge that allows different conformations. Such flexible chemical structure bring about ability to Curcumin to modulate or interfere several biochemical pathways— a versatility towards broad-spectrum of targets.

Various molecular targets of curcumin include inflammatory molecules, enzymes, growth factors, transcription factors, kinases, receptors and metal ions. 

Analysis of Chemical Structure vis-a-vis Biological Activity
  • As previously mentioned, through covalent and non-covalent interactions Curcumin exhibits modulating effects on a wide number of protein molecules either indirectly or directly
  • Studies using molecular modelling and docking—biophysical tools have shown that curcumin as well as its analogs directly interact with various target proteins such as inflammatory molecules, enzymes, carrier proteins and nucleic acids, for example tumor necrosis factor-α, cyclooxygenase-1 and 2 etc
  • Curcumin and its anmargin-bottom:15px;logs bindings to most of these proteins at very low concentrations (Binding constant has been detected in the nM-μM range)

As discussed earlier, because of its inherent chemical functionality—can exhibit several different conformations—directly binds to diverse proteins with high affinity. The moieties such as phenyl, hydroxyl, methoxyl and the 1,3-dicarbonyl functional groups offer a strong and directed electrostatic interaction helping enhanced favourable binding-free energies.

Furthermore, Curcumin displays additional chemical functionality as it undergoes the “keto-enol tautomerism” as a result of the β-diketone moiety. It has been observed that enol form— the predominant form allows the midsection of the molecule to act as both hydrogen bond donor and acceptor; it may also act as a chelator for positively charged metals present in the active sites of target proteins.  

Reference: Majeed M. and Badmaev V. Curcuminoids-Pharmacological Actions Including Pre-Clinical  and  Clinical Evaluations. In: Curcuminoids: Antioxidant phytonutrients, New Jersey, Nutriscience Publishers Inc., 2003;pp. 32