INHIBITOR DESIGN and SYNTHESIS

The rational design of enzyme inhibitors is being pursued in the laboratory in the context of cytochrome P450 enzymes, heme oxygenases, severalMycobacterium tuberculosis target proteins and, in a collaborative effort with the group of Charles Craik, the Kaposi sarcoma protease.

The synthesis of a series of molecules targeted to the active site of KSHV protease produced low activity inhibitors (Kd in the mM range) of the enzyme. Analysis of the crystal structure indicates that the active site crevice is very shallow, making the design of selective agents directed at this site highly challenging. We have therefore shifted our attention for the near future to the dimer interface of the protein. The low affinity constant of the dimer, a problem that must be solved to develop a good inhibitor assay, makes the design of agents that disrupt the interface an attractive route to inhibition of the enzyme.

In the case of cytochrome P450 enzymes, we are collaborating with the group of I. D. Kuntz in approaches to the computer-assisted design of inhibitors for hemoproteins in general. We are also particularly interested in high specificity irreversible inhibitors of the CYP4 class of enzymes that are able to differentiate between members of the class itself, and members of other P450 classes. This rational inhibitor design approach is being complemented by library screen methods.

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