title: Drug design from the cryptic inhibitor envelope.
abstract: Conformational dynamics plays an important role in enzyme catalysis, allosteric regulation of protein functions and assembly of macromolecular complexes. Despite these well-established roles, such information has yet to be exploited for drug design. Here we show by nuclear magnetic resonance spectroscopy that inhibitors of LpxC--an essential enzyme of the lipid A biosynthetic pathway in Gram-negative bacteria and a validated novel antibiotic target--access alternative, minor population states in solution in addition to the ligand conformation observed in crystal structures. These conformations collectively delineate an inhibitor envelope that is invisible to crystallography, but is dynamically accessible by small molecules in solution. Drug design exploiting such a hidden inhibitor envelope has led to the development of potent antibiotics with inhibition constants in the single-digit picomolar range. The principle of the cryptic inhibitor envelope approach may be broadly applicable to other lead optimization campaigns to yield improved therapeutics.
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Chul-Jin
authors.initials: CJ
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Duke University, Durham, North Carolina 27708, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Javaria
authors.initials: J
authors.lastname: Najeeb
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Jinshi
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Chemistry, Duke University, Durham, North Carolina 27708, USA.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Gopalaswamy
authors.affiliation: Inserm, Univ. Lille, CHU Lille, Institut Pasteur de Lille, CNRS, U1019-UMR 8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Titecat
authors.affiliation: Inserm, Univ. Lille, CHU Lille, Institut Pasteur de Lille, CNRS, U1019-UMR 8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Sebbane
authors.affiliation: Inserm, Univ. Lille, CHU Lille, Institut Pasteur de Lille, CNRS, U1019-UMR 8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Lemaitre
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.|Department of Chemistry, Duke University, Durham, North Carolina 27708, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Toone
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.|Department of Chemistry, Duke University, Durham, North Carolina 27708, USA.
authors.forename: Pei
authors.initials: P
authors.lastname: Zhou
mesh_terms: D000581:Amidohydrolases / Q000187:drug effects* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003460:Crystallization; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects* / Q000378:metabolism; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D058990:Molecular Targeted Therapy; D011487:Protein Conformation; D011550:Pseudomonas aeruginosa; D013912:Threonine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; C525369:CHIR 090; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C000609007:LPC-011; D008024:Ligands; D013912:Threonine; D000581:Amidohydrolases; C514484:LpxC deacetylase, Pseudomonas; C097307:UDP-3-O-acyl-N-acetylglucosamine deacetylase