title: Development of quinone analogues as dynamin GTPase inhibitors.
abstract: Virtual screening of the ChemDiversity and ChemBridge compound databases against dynamin I (dynI) GTPase activity identified 2,5-bis-(benzylamino)-1,4-benzoquinone 1 as a 273 ± 106 μM inhibitor. In silico lead optimization and focused library-led synthesis resulted in the development of four discrete benzoquinone/naphthoquinone based compound libraries comprising 54 compounds in total. Sixteen analogues were more potent than lead 1, with 2,5-bis-(4-hydroxyanilino)-1,4-benzoquinone (45) and 2,5-bis(4-carboxyanilino)-1,4-benzoquinone (49) the most active with IC50 values of 11.1 ± 3.6 and 10.6 ± 1.6 μM respectively. Molecular modelling suggested a number of hydrogen bonding and hydrophobic interactions were involved in stabilization of 49 within the dynI GTP binding site. Six of the most active inhibitors were evaluated for potential inhibition of clathrin-mediated endocytosis (CME). Quinone 45 was the most effective CME inhibitor with an IC50(CME) of 36 ± 16 μM.
authors.affiliation: Centre for Chemical Biology, Chemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia.
authors.forename: Kylie A
authors.initials: KA
authors.lastname: MacGregor
authors.affiliation: Centre for Chemical Biology, Chemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia; Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
authors.forename: Mohammed K
authors.initials: MK
authors.lastname: Abdel-Hamid
authors.affiliation: Centre for Chemical Biology, Chemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia.
authors.forename: Luke R
authors.initials: LR
authors.lastname: Odell
authors.affiliation: Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
authors.forename: Ngoc
authors.initials: N
authors.lastname: Chau
authors.affiliation: Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
authors.forename: Ainslie
authors.initials: A
authors.lastname: Whiting
authors.affiliation: Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Robinson
authors.affiliation: Centre for Chemical Biology, Chemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia. Electronic address: Adam.McCluskey@newcastle.edu.au.
authors.forename: Adam
authors.initials: A
authors.lastname: McCluskey
mesh_terms: D000818:Animals; D002460:Cell Line; D002966:Clathrin / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D034284:Dynamin I / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D011809:Quinones / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D002966:Clathrin; D004791:Enzyme Inhibitors; D011809:Quinones; D034284:Dynamin I; D020558:GTP Phosphohydrolases
keywords: Dynamin; Dynamin inhibitors; Endocytosis; Modelling; Quinones