Reversible enzyme inhibitors

Oxford spinout InhibOx has just announced the launch of a free service, devised by Professor Graham Richards, to help in the search for new drugs.

DrugFinder focuses on inhibitors – molecules that binds to an enzyme to decrease its activity. Many drug molecules are inhibitors (examples include everything from antiretroviral drugs to treat HIV to pills such as Viagra).

The new service enables researchers and biotech firms to submit the crystal structure of a target protein with an inhibitor bound in the active site [rather like a key-shape in a keyhole preventing any keys from activating it] and then screen its database of molecules for potentially superior inhibitors for that protein.

The system is a collaboration between InhibOx and the National Foundation for Cancer Research and follows on from the highly successful Screensaver Lifesaver project.

Super sensors
Technology invented by Oxford researchers to monitor pH level in oil wells is to be adapted for other industries in a tie-up with Phathom Nanosensors Ltd.

The technology was developed by Professor Richard Compton and uses solid state electrochemical sensors that are self-calibrating and can be used in many situations where use of conventional glass electrodes is impracticable.

Oxford University’s technology transfer company, Isis Innovation has licensed the technology to Phathom with targets including pharmaceutical, food & beverage, and chemical manufacturers.

Oxford's Dept of Chemistry






Reversible inhibitors bind to enzymes with non-covalent interactions such as hydrogen bonds, hydrophobic interactions and ionic bonds. Multiple weak bonds between the inhibitor and the active site combine to produce strong and specific binding. In contrast to substrates and irreversible inhibitors, reversible inhibitors generally do not undergo chemical reactions when bound to the enzyme and can be easily removed by dilution or dialysis.

There are three kinds of reversible enzyme inhibitors. They are classified according to the effect of varying the concentration of the enzyme's substrate on the inhibitor.[2]

* In competitive inhibition, the substrate and inhibitor cannot bind to the enzyme at the same time, as shown in the figure on the left. This usually results from the inhibitor having an affinity for the active site of an enzyme where the substrate also binds; the substrate and inhibitor compete for access to the enzyme's active site. This type of inhibition can be overcome by sufficiently high concentrations of substrate, i.e., by out-competing the inhibitor. Competitive inhibitors are often similar in structure to the real substrate (see examples below).

* In mixed inhibition, the inhibitor can bind to the enzyme at the same time as the enzyme's substrate. However, the binding of the inhibitor affects the binding of the substrate, and vice versa. This type of inhibition can be reduced, but not overcome by increasing concentrations of substrate. Although it is possible for mixed-type inhibitors to bind in the active site, this type of inhibition generally results from an allosteric effect where the inhibitor binds to a different site on an enzyme. Inhibitor binding to this allosteric site changes the conformation (i.e., tertiary structure or three-dimensional shape) of the enzyme so that the affinity of the substrate for the active site is reduced.

* Non-competitive inhibition is a form of mixed inhibition where the binding of the inhibitor to the enzyme reduces its activity but does not affect the binding of substrate. As a result, the extent of inhibition depends only on the concentration of the inhibitor.