Modelling of the interactions of some inhibitors with the farnesyl proteintransferase by biodock. A stochastic approach to the automated docking of ligands to biomacromolecules.

Oncogenic mutations of the mammalian Ras protooncogene have been implicated in 20%-30% of all human cancers. A key step in a series of posttranslation al modifications of the oncogene product Ras is the S- farnesylation of a c ystein residue near the C-terminus in a reaction catalyzed by the enzyme fa rnesyltransferase (FTase) using farnesyl diphosphate (FPP). This step is im portant for the association of the GTP-binding Ras protein to the inner sur face of the plasma membrane, where it mediates cellular trasformations. Thu s, FTase is a current target for small molecule inhibitors. Two types of FT ase inhibitors have been designed on the basis of the structure of the two substrates of the reaction, farnesyl diphosphate mimics and Ras CAAX tetrap eptide mimics. Some well known inhibitors have been docked to the FTase str ucture, as recently obtained by X ray crystallographic analysis, in order t o highlight possible interaction differences.