Binding sites are the key to anti-cancer therapy
Retinoids and rexinoids can interfere with, and in some cases totally prevent, the progression of a cell in its development to tumour status. Apoptosis, or programmed cell death can be induced directly using retinoids and rexinoids during chemotherapy. These molecules can also prevent differentiation of a progenitor cell induced by a tumour promoter. The EU funded ANTICANCER RETINOIDS project aimed to develop new types of retinoid that possessed specific cognate ligands. Biological systems rely on ligands for binding to form stable complexes. Specially designed cognate ligands would then selectively bind to molecules in various pathways to effect an anti-tumour action. As an integral part of this research, scientists at the Departamento de Química Orgánica in Galicia, Spain investigated the mechanics of ligand binding to retinoid receptors, known as RXRs (retinoid X receptors) and RARs (retinoic acid receptors). The cognate ligands could then be ranked according to their ability to adapt to the shape of the binding site. The next step was to then engineer ligands to specifically bind with a retinoid receptor. The study delved into the energetics of bonding. The electrostatic and van der Waals forces that come into play for attraction at binding sites were investigated. For example, the carboxylic groups present in RXRs and RARs possess a difference in polarity. This means there is a large difference in interaction energy between these two receptors and the same ligand. Based on the outcomes of this research, project partners aimed to build RXR sites utilising the phenomenon of binding site polarity. This can then be harnessed to create the specific mode of action required in anti-cancer drug therapy.
