As patients begin treatment the selective pressures of anti-

As patients begin treatment the selective pressures of anti-virals will favor drug resistant quasispecies. Mutations that confer the most severe resistance in the clinic occur where inhibitors protrude from the consensus volume defining the substrate envelope, as these changes selectively weaken inhibitor binding AZD-7762 without compromising the substrate binding. Both FDA-approved boceprevir and telaprevir exhibit a ketoamide moiety with the catalytic serine nucleophile and these inhibitors generate a covalent, albeit reversible, enzyme-inhibitor complex. Additional NS3/ 4A-targeting compounds, non-covalent reversible peptidomimetic macrocycle inhibitors such as TMC435350, MK-7009, ITMN- 191, BILN-2061, BMS-791325, GS-9256 and ABT-450, have also been a subject of extensive evaluation and 325715-02-4 supplier clinical testing in the recent years. These macrocyclic inhibitors exhibit an overlapping, albeit distinct, resistance profile compared with FDA-approved boceprevir and telaprevir ketoamides. Because of its functional importance in the HCV life cycle, NS3/4A is an attractive anti-viral drug target. The current inhibitors can be roughly divided into two classes, macrocyclic and linear, peptidomimetic a-ketoamide derivatives. Peptidomimetic macrocyclic ciluprevir that non-covalently binds the NS3/4A active site failed clinical trials because of its cardiotoxicity. In turn, the linear peptidomimetic a-ketoamides, telaprevir and boceprevir, that bind covalently, albeit reversibly, to the active site Ser-139, have recently been approved by the FDA for clinical use. To compensate for the shallow active site groove architecture both a-ketoamides exploit interactions with catalytically non-essential amino acid residues. To identify additional, structurally similar scaffolds in the NCI/ DTP database and to perform scaffold hopping, we employed in silico SAR optimization using compounds 1, 3 and 5 as seeds. The Tanimoto distance was as used as a chemical similarity measure of the novel compounds relative to the seeds. For each seed structure, 250 close derivatives were selected from the NCI/ DTP database. The full-atom ligand structures of the resulting 750-compound focused sub-library were then minimized using the Q-MOL minimization protocol. The structures of 665 compounds were su