Effects of fluorine on enzyme-inhibitor interactions.
Effects of fluorine on enzyme-inhibitor interactions.
New insight into molecular recognition at the active sites of enzymes has been revealed by looking at the effect of fluorine on recognition between thrombin and some of its inhibitors. Our knowledge of structure-based drug design can be developed by examining the unusual effects that fluorine may have on intermolecular interactions.
Currently there are more than 150 fluorinated drugs in clinical use. However, little is known about how fluorine substitution affects molecular recognition properties such as protein binding affinity and selectivity. Fran?ois Diederich and his co-workers in Switzerland have undertaken fluorine scans of thrombin inhibitors to provide meaningful protein-ligand structure-activity relationships. They performed the scans to assess the fluorophilicity of the enzyme active site and to study the effect of H to F substitutions on the thermodynamics of protein-ligand interactions. Fluorine scans of the thrombin inhibitor phenylamidinium residue, which extends into the active site of the enzyme, revealed that lowering the basicity of the residue is detrimental to the pharmacokinetic properties of the inhibitor because it reduces its binding selectivity. Scientists in the field will be interested by the observations of favourable C-F .CN interactions that are backed up by detailed analysis of the Cambridge Structural Database. Additionally, after fluorine substitution, a decrease was found in both the p Ka values and the inhibitory constants ( Ki) against thrombin and trypsin. These are important results for the future design of thrombin-selective inhibitors.
Diederich, who is based in Zurich, says that much of the work has only been possible through an intense and successful collaboration with scientists at Roche, Basel. He is ’strongly convinced that a full understanding of the effects of fluorine on protein binding affinity and selectivity will greatly benefit future structure-based design and lead to optimisation in medicinal chemistry’. He believes that ’fluorine scans used to map the fluorophilicity/fluorophobicity of enzyme active sites and protein hot-spots will continue to provide fundamentally new information on molecular recognition principles’.
Eleanor Riches
References
J Olsen et al., Org. Biomol. Chem., 2004, 2,1339 <MAN>b402515f</MAN>
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