small molecule inhibitors of the ledgf site of human immunodeficiency virus integrase identified by fragment screening and structure based design小分子抑制剂的ledgf网站确认的人类免疫缺陷病毒整合酶片段筛选和基于结构的设计.pdf

Small Molecule Inhibitors of the LEDGF Site of Human Immunodeficiency Virus Integrase Identified by Fragment Screening and Structure Based Design 1 2¤a 2 2 2 2 Thomas S. Peat *, David I. Rhodes , Nick Vandegraaff , Giang Le , Jessica A. Smith , Lisa J. Clark , 2 2 2 1 1 Eric D. Jones , Jonathan A. V. Coates , Neeranat Thienthong , Janet Newman , Olan Dolezal , 3 3 3 3 2¤b Roger Mulder , John H. Ryan , G. Paul Savage , Craig L. Francis , John J. Deadman 1 CSIRO Materials, Science and Engineering, Parkville, Victoria, Australia, 2 Avexa Ltd, Melbourne, Victoria, Australia, 3 CSIRO Materials, Science and Engineering, Clayton, Victoria, Australia Abstract A fragment-based screen against human immunodeficiency virus type 1 (HIV) integrase led to a number of compounds that bound to the lens epithelium derived growth factor (LEDGF) binding site of the integrase catalytic core domain. We determined the crystallographic structures of complexes of the HIV integrase catalytic core domain for 10 of these compounds and quantitated the binding by surface plasmon resonance. We demonstrate that the compounds inhibit the interaction of LEDGF with HIV integrase in a proximity AlphaScreen assay, an assay for the LEDGF enhancement of HIV integrase strand transfer and in a cell based assay. The compounds identified represent a potential framework