title: Non-bisphosphonate inhibitors of isoprenoid biosynthesis identified via computer-aided drug design.
abstract: The relaxed complex scheme, a virtual-screening methodology that accounts for protein receptor flexibility, was used to identify a low-micromolar, non-bisphosphonate inhibitor of farnesyl diphosphate synthase. Serendipitously, we also found that several predicted farnesyl diphosphate synthase inhibitors were low-micromolar inhibitors of undecaprenyl diphosphate synthase. These results are of interest because farnesyl diphosphate synthase inhibitors are being pursued as both anti-infective and anticancer agents, and undecaprenyl diphosphate synthase inhibitors are antibacterial drug leads.
authors.affiliation: Department of Chemistry & Biochemistry, University of California San Diego, 9500 Gilman Drive, Mail Code 0365, La Jolla, CA 92093, USA. jdurrant@ucsd.edu
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Durrant
authors.forename: Rong
authors.initials: R
authors.lastname: Cao
authors.forename: Alemayehu A
authors.initials: AA
authors.lastname: Gorfe
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Jikun
authors.initials: J
authors.lastname: Li
authors.forename: Anna
authors.initials: A
authors.lastname: Sankovsky
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D017076:Computer-Aided Design; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000201:enzymology*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; D051228:Geranyltranstransferase; C023266:undecaprenyl pyrophosphate synthetase