Novel ATIC Inhibitor Design via Fragment-Tethering Strategy

• 作 者: Lan Xu Chenglong Li Arthur J.Olson Ian A.Wilson
• 机 构: Department of Molecular Biology , The Scripps Research Institute,10550 North Torrey Pines Road, La J
• 出 处: 2005 WHTS3rd Annual Congress of International Drug Discovery
• 发表日期: 2005年12期

　　The bifunctional enzyme aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase)/IMP cyclohydrolase (ATIC), catalyzes the penultimate and final steps in the de novo purine biosynthesis pathway that produces IMP, and hence, is a potential target for antineoplastic intervention.We have focused on the identification of novel, non-folate based inhibitors that selectively inhibit AICAR Tfase activity, which may cause less severe cytotoxicity than traditional anti-folates, such as methotrexate.Here, we present a fragrnentbased approach for ATIC inhibition combining X-ray crystallography and molecular modeling.A systematic search for novel inhibitors of AICAR Tfase utilizing molecular docking coupled with in vitro enzymatic assay enabled discovery of several novel non-folate based inhibitors.Through detailed structural and computational analysis of previous sulfonyl-containing inhibitor complex structures, several low molecular weight fragments were identified that bound to discrete regions of AICAR Tfase active sites.Novel inhibitors were then designed through fragment tethering using different covalent linker groups and their binding modes were predicted by molecular docking.Enzymatic inhibition assays on selected potential leads and their complexed crystal structures will facilitate the next round of inhibition elaboration.