Models of ternary complexes for nonpeptidic farnesyltransferase inhibitors: Insights into structure-based screen and design of potential anticancer therapeutics

Farnesyltransferase (FT) inhibitors can repress tumor cell proliferation wi thout substantially interfering with normal cell growth and are thus promis ing in cancer treatment. A detailed knowledge of how substrates and inhibit ors bind to FT at the atomic level can expedite screening and rational desi gn of improved FT inhibitors. Here we report theoretical models of the FT c omplexed with FPP and the potent nonpeptidic inhibitor SCH 56580 and other inhibitor-FPP-FT ternary complexes derived from the docking studies prior t o any crystal structures of the FT liganded with nonpeptidic inhibitors. On the basis of these models we evaluate the roles of FPP, Zn2+ and the zinc- coordinated water molecule in inhibitor binding, and propose the structural determinants of binding of nonpeptidic FT inhibitors. Furthermore, we sugg est the use of the FPP-FT binary complex as a novel and effective drug targ et structure for screening and rational design of improved FT inhibitors.