Janssen Pharmaceutica Nv

Johnson & Johnson Pharmaceutical Research & Development, LLC

Frank A Lewandowski

Cynthia M Milligan

Richard Scott Alexander

Celine Schalk-Hihi

Diane M Maguire

Marta Cristina Abad

Dionisios Rentzeperis

Aihua Wang

Kristi A Leonard

Roger Francis Bone

Brett A Tounge

Joseph Kent Barbay

Barry A Springer

Kenneth Rhodes

Lawrence C Kuo

Matthew J Todd

Robert Scannevin

John Curtis Spurlino

Paul F Jackson

Bruce L Grasberger

Ingrid Christa Deckman

Ludmila A Barnakova

Carsten Schubert

Carl L Manthey

Beverley Moore

John O'Neill

Hossein B Askari

Carl Crysler

Barry Springer

Robert H Scannevin

Kenneth J Rhodes

The crystal structure of the ligand binding domain of ERR-&#x3b1; in complex with a ligand that forms a reversible thioether bond to Cys325 of ERR-&#x3b1;, methods to measure dissociation rates for ligands that form reversible covalent bonds, and methods to design ligands that form reversible covalent bonds for use as modulators of ERR-&#x3b1; activity are disclosed. The crystal structure and methods provide a novel molecular mechanism for modulation of the activity of ERR-&#x3b1; and provide the basis for rational drug design to obtain potent specific ligands for use as modulators of the activity of this new drug target.

Methods to measure dissociation rates for ligands that form reversible covalent bonds

The present invention includes a crystal comprising a complex of the pro form of a matrix metalloprotease (proMMP) and a small-molecule allosteric processing inhibitor that inhibits that activation of the proMMP, methods for identifying small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP, and methods of treatment using small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP. The present invention relates to the crystal structure of a complex of proMMP9 bound to a small-molecule allosteric processing inhibitor that inhibits activation of proMMP9. The invention further relates to the use of the methods and the crystal and related structural information for designing, selecting and/or optimizing small-molecule allosteric processing inhibitors that inhibit activation of proMMP9 and proMMP9 homologues. The present invention also relates to the use of small-molecule allosteric processing inhibitors for the treatment of diseases mediated by inappropriate matrix metalloproteinase (MMP) activity.

Methods of treatment using allosteric processing inhibitors for matrix metalloproteinases

Methods for designing, selecting and/or optimizing allosteric processing inhibitors for matrix metalloproteinases

Crystal structure of the pro form of a matrix metalloproteinase and an allosteric processing inhibitor

Co-crystallization of ERR-&#x3b1; with a ligand that forms a reversible covalent bond

A number of soluble engineered forms of MGLL that are suitable for high-throughput screening and protein crystallization, as well as a crystallized form of monoacylglycerol lipase protein (MGLL) and descriptions of the X-ray diffraction patterns are disclosed. The engineered constructs of MGLL permit the expression and purification of protein suitable for crystallography or high-throughput screening and identification of ligands, which can function as active agents to MGLL. The X-ray diffraction patterns allow the three dimensional structure of MGLL to be determined at atomic resolution so that ligand binding sites on MGLL can be identified and the interactions of ligands with MGLL amino acid residues can be modeled. Models prepared using such maps permit the design of ligands which can function as active agents which include, but are not limited to, those that function as inhibitors of MGLL.

Protein engineering of monoacylglycerol lipase (MGLL)

Crystal structure of monoacylglycerol lipase (MGLL)

A number of soluble engineered forms of MGLL that are suitable for high-throughput screening and protein crystallization, as well as a crystallized forms of monoacylglycerol lipase protein (MGLL) and descriptions of the X-ray diffraction patterns are disclosed. The engineered constructs of MGLL permit the expression and purification of protein suitable for crystallography or high-throughput screening and identification of ligands, which can function as active agents to MGLL. The X-ray diffraction patterns allow the three dimensional structure of MGLL to be determined at atomic resolution so that ligand binding sites on MGLL can be identified and the interactions of ligands with MGLL amino acid residues can be modeled. Models prepared using such maps permit the design of ligands which can function as active agents which include, but are not limited to, those that function as inhibitors of MGLL.

Alternative crystal form of monoacylglycerol lipase (MGLL)

A method for the identification of novel compounds that interact and stabilize the ligand binding domain of estrogen-related receptor gamma (ERR&#x3b3;), a methodology for producing diffraction quality crystal structures in the presence of antagonist and agonist ligands, including Bisphenol A, and the identification of novel biologically-active compounds that have an effect on the transcriptional-activating activity of ERR&#x3b3; are disclosed.

Crystallized structure of estrogen related receptor gamma in complex with bisphenol A

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Washington Crossing, PA, United States of America

Frank A Lewandowski