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Pharmaceuticals (Basel). 2018 Feb 16;11(1). pii: E22. doi: 10.3390/ph11010022.

A Novel Interaction Between the TLR7 and a Colchicine Derivative Revealed Through a Computational and Experimental Study.

Author information

1
Department of Physics, University of Alberta, AB T6G 2E1 Edmonton, Canada. fgentile@ualberta.ca.
2
Istituto Dalle Molle di Studi Sull'intelligenza Artificiale (IDSIA), Scuola Universitaria Professionale della Svizzera Italiana (SUPSI), Università della Svizzera Italiana (USI), CH-6928 Manno, Switzerland. deriu.marco@gmail.com.
3
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, AB T6G 2H1 Edmonton, Canada. kbarakat@ualberta.ca.
4
Istituto Dalle Molle di Studi Sull'intelligenza Artificiale (IDSIA), Scuola Universitaria Professionale della Svizzera Italiana (SUPSI), Università della Svizzera Italiana (USI), CH-6928 Manno, Switzerland. andrea.danani@gmail.com.
5
Department of Physics, University of Alberta, AB T6G 2E1 Edmonton, Canada. jackt@ualberta.ca.
6
Department of Mechanical and Aerospace Engineering, Politecnico di Torino, 10129 Torino, Italy. jackt@ualberta.ca.
7
Department of Oncology, University of Alberta, AB T6G 1Z2 Edmonton, Canada. jackt@ualberta.ca.

Abstract

The Toll-Like Receptor 7 (TLR7) is an endosomal membrane receptor involved in the innate immune system response. Its best-known small molecule activators are imidazoquinoline derivatives such as imiquimod (R-837) and resiquimod (R-848). Recently, an interaction between R-837 and the colchicine binding site of tubulin was reported. To investigate the possibility of an interaction between structural analogues of colchicine and the TLR7, a recent computational model for the dimeric form of the TLR7 receptor was used to determine a possible interaction with a colchicine derivative called CR42-24, active as a tubulin polymerization inhibitor. The estimated values of the binding energy of this molecule with respect to the TLR7 receptor were comparable to the energies of known binders as reported in a previous study. The binding to the TLR7 was further assessed by introducing genetic transformations in the TLR7 gene in cancer cell lines and exposing them to the compound. A negative shift of the IC50 value in terms of cell growth was observed in cell lines carrying the mutated TLR7 gene. The reported study suggests a possible interaction between TLR7 and a colchicine derivative, which can be explored for rational design of new drugs acting on this receptor by using a colchicine scaffold for additional modifications.

KEYWORDS:

TLR7; colchicine; imiquimod; innate immune system; off-target interaction

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