A novel interaction between the TLR7 and a colchicine derivative revealed through a computational and experimental study

Gentile, Francesco; Deriu, Marco A.; Barakat, Khaled; Danani, Andrea; Tuszynski, Jack

doi:10.3390/ph11010022

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Journal article

A novel interaction between the TLR7 and a colchicine derivative revealed through a computational and experimental study

Gentile, Francesco Department of Physics, University of Alberta, AB T6G 2E1 Edmonton, Canada
Deriu, Marco A. Istituto Dalle Molle di studi sull'intelligenza artificiale (IDSIA), Facoltà di scienze informatiche, Università della Svizzera italiana, Svizzera
Barakat, Khaled Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, AB T6G 2H1 Edmonton, Canada
Danani, Andrea Istituto Dalle Molle di studi sull'intelligenza artificiale (IDSIA), Facoltà di scienze informatiche, Università della Svizzera italiana, Svizzera
Tuszynski, Jack Department of Physics, University of Alberta, AB T6G 2E1 Edmonton, Canada - Department of Mechanical and Aerospace Engineering, Politecnico di Torino, 10129 Torino, Italy - Department of Oncology, University of Alberta, AB T6G 1Z2 Edmonton, Canada

16.02.2018

Published in:

Pharmaceuticals. - 2018, vol. 11, no. 1, p. 22

English 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.

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