One molecule hits two targets

16 May 2016 Scientists in NUS discovered new small synthetic molecules with the aim of each molecule inhibiting two enzymes simultaneously, thus giving rise to potential anticancer properties.

This study led by Prof CHUI Wai Keung from the Department of Pharmacy in NUS has constructed new organic molecules that linked essential structural features which are required to bind to the enzymes dihydrofolate reductase (DHFR) and thiredoxin reductase (TrxR). The resultant most active singular molecule demonstrated inhibitory activity against the two enzymes in micromolar concentrations (DHFR IC50 value = 2.4 µM, TrxR IC50 (60 min) value = 10.1 µM). The molecules also showed growth inhibition against the MCF-7 and HCT-116 cancer cells. Computational experiments rationalised their binding modes to both enzymes with high docking scores; thus supporting the results obtained from the enzymatic and cellular inhibitory assays (see Figure).

DHFR and TrxR are two metabolic enzymes which are implicated in cancer cell growth and survival. They are involved in different metabolic pathways. Molecules that inhibit these enzymes have the potential to be developed into anticancer drugs. The advantages of this dual-target approach by one molecule are: (i) reduce the number of medications that a patient needs to take (ii) reduce the buildup of drug resistance; and (iii) provide synergistic inhibitory effects of the combinatorial actions on cancer cells.

Currently, in the market there are some anticancer drugs that are hitting more than one target each time. This study is a first report in literature that presents a systematic approach to the design of molecules that are constructed to hit more than one target. The use of combinatorial treatment of known inhibitors of the targets in the initial study provides information on whether synergistic pharmacological effects are achievable. This information provides the basis for the design of dual-target molecules. Moving forward, a similar approach can be used to design new molecules that can be potentially used to treat other diseases.

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Figure shows the binding of the most active molecule at the active sites of dihydrofolate reductase (left) and thioredoxin reductase (right) with high docking scores. [Image credit: Chui WK]



Ng HL, Chen SY, Chew EH, Chui WK. “Applying the designed multiple ligands approach to inhibit dihydrofolate reductase and thioredoxin reductase for antiproliferative activity” Eur J Med Chem. 115 (2016) 63.