In silico Investigation of Curcumin as a Positive Allosteric Modulator of a7‐Nicotinic Acetylcholine Receptors

Polyphenolic compound curcumin isolated from turmeric, has been shown to exhibit antioxidant, anti‐inflammatory, anticancer, and antimicrobial effects. Nicotinic acetylcholine (nACh) receptors are important members of the ligand‐gated ion channel family. Activation of neuronal a7‐nACh receptors produces analgesic effects in laboratory animal and human studies . Recently published experimental results of electrophysiological studies 1 indicate that curcumin tested on the function of the a7‐subunit of the human nicotinic acetylcholine (a7‐nACh) receptor caused a significant potentiation of currents induced by acetylcholine. It was suggested 1 that curcumin is a positive allosteric modulator (PAM) of a7‐nACh receptor and decreased desensitization of the receptor. Mechanism of action by which the curcumin interact with the nicotinic acetylcholine (a7‐nACh) receptor is not fully understood although research indicates it may bind to a currently unidentified allosteric binding site at the interface between the transmembrane region and the extracellular domain. Using in silico techniques, such as molecular docking and recently published revised structural model 2 of open and closed conformations of the receptor, we have identified sites of strong interaction of curcumin with particular functional groups in intersubunit transmembrane site. We used two independent docking programs to improve reliability of our predictions. Our results correlated well with previously identified key binding site residues of positive allosteric modulators of the nicotinic acetylcholine (a7‐nACh) receptor. We performed virtual screening of the set of structural analogs of curcumin and identified several compounds with high binding affinities and conserved key residues interaction similar to curcumin. This work provide explanation of molecular basis of the interactions between curcumin and curcumin analogs and nicotinic acetylcholine (nACh) receptor. It is likely that structure of curcumin analogs that we identified can aid design of future therapeutic agents with analgesic effects.1 Curcumin Acts as a Positive Allosteric Modulator of α 7 -Nicotinic Acetylcholine Receptors and Reverses Nociception in Mouse Models of Inflammatory Pain . J Pharmacol Exp Ther . 2018 Apr ; 365 ( 1 ): 190 – 200 . El Nebrisi EG , Bagdas D , Toma W , Al Samri H , Brodzik A , Alkhlaif Y , Yang KS , Howarth FC , Damaj IM , Oz M.