Abstract: Methods for rapidly identifying drug candidates that can bind to an enzyme at both a common ligand site and a specificity ligand site, resulting in high affinity binding. The bi-ligand drug candidates are screened from a focused combinatorial library where the specific points of variation on a core structure are optimized. The optimal points of variation are identified by which atoms of a ligand bound to the common ligand site are identified to be proximal to the specificity ligand site. As a result, the atoms proximal to the specificity ligand site can then be used as a point for variation to generate a focused combinatorial library of high affinity drug candidates that can bind to both the common ligand site and the specificity ligand site. Different candidates in the library can then have high affinity for many related enzymes sharing a similar common ligand site.

Abstract: Compounds and compositions for modulating the activity of p38 kinases are provided, including p38?, and p38? kinase. Methods for treating, preventing or ameliorating one or more symptoms of a p38 kinase mediated disease or disorder are also provided.

Abstract: A method for preferentially observing an exposed position (1c) of a macromolecule. A sample is obtained having a macromolecule (1a) with a first proton (1) and a second molecule (2a) with a second proton (2); then applying a magnetic field (4) to the sample and irradiating the sample with a pulse sequence (5) that preferentially demagnetizes protons of the macromolecule (1,3) relative to the second proton (2); allowing the second proton (2) to exchange (6) with an exposed proton (1) of the macromolecule; and detecting the magnetization from the relatively magnetized second proton (2), which is now bound to the exposed position (1c) of the macromolecule. The invention also provides a method for observing a position in the macromolecule that bind a ligand.

Abstract: A method for preferentially observing an exposed position (1c) of a macromolecule. A sample is obtained having a macromolecule (1a) with a first proton (1) and a second molecule (2a) with a second proton (2); then applying a magnetic field (4) to the sample and irradiating the sample with a pulse sequence (5) that preferentially demagnetizes protons of the macromolecule (1, 3) relative to the second proton (2); allowing the second proton (2) to exchange (6) with an exposed proton (1) of the macromolecule; and detecting the magnetization from the relatively magnetized second proton (2), which is now bound to the exposed position (1c) of the macromolecule. The invention also provides a method for observing a position in the macromolecule that bind a ligand.

Abstract: Methods for rapidly identifying drug candidates that can bind to an enzyme at both a common ligand site and a specificity ligand site, resulting in high affinity binding. The bi-ligand drug candidates are screened from a focused combinatorial library where the specific points of variation on a core structure are optimized. The optimal points of variation are identified by which atoms of a ligand bound to the common ligand site are identified to be proximal to the specificity ligand site. As a result, the atoms proximal to the specificity ligand site can then be used as a point for variation to generate a focused combinatorial library of high affinity drug candidates that can bind to both the common ligand site and the specificity ligand site. Different candidates in the library can then have high affinity for many related enzymes sharing a similar common ligand site.

Abstract: The invention provides a method for separating two or more subsets of polypeptides within a set of polypeptides. The method includes the steps of: (a) determining a sequence comparison signature for each amino acid sequence in a set of amino acid sequences, wherein the sequence comparison signature includes pairwise comparison scores for the amino acid sequence compared to each of the other amino acid sequences in the set; (b) constructing a distance arrangement including the sequence comparison signatures related according to the distance between each of the sequence comparison signatures; and (c) identifying a first and second cluster of sequence comparison signatures in the distance arrangement, wherein the first cluster includes sequence comparison signatures for polypeptides having a similar protein fold or biological function, the protein fold or function being different compared to a protein fold or function of polypeptides having sequence comparison signatures in the second cluster.

Abstract: The invention provides a method for identifying a pharmacocluster. The method includes the steps of (a) determining bound conformations of a ligand bound to different polypeptides, and (b) clustering two or more bound conformations of the ligand having substantially the same bound conformation, thereby identifying a pharmacocluster. The invention also provides a method for identifying a member of a pharmacocluster. The invention also provides a method for identifying a polypeptide pharmacofamily. The method includes the steps of (a) determining bound conformations of a ligand bound to different polypeptides of a polypeptide family, and (b) identifying two or more bound conformations of the ligand having substantially different bound conformations, thereby identifying at least two polypeptide pharmacofamilies exhibiting binding specificity for the two or more substantially different bound conformations of the ligand.

Abstract: Methods for rapidly identifying drug candidates that can bind to an enzyme at both a common ligand site and a specificity ligand site, resulting in high affinity binding. The bi-ligand drug candidates are screened from a focused combinatorial library where the specific points of variation on a core structure are optimized. The optimal points of variation are identified by which atoms of a ligand bound to the common ligand site are identified to be proximal to the specificity ligand site. As a result, the atoms proximal to the specificity ligand site can then be used as a point for variation to generate a focused combinatorial library of high affinity drug candidates that can bind to both the common ligand site and the specificity ligand site. Different candidates in the library can then have high affinity for many related enzymes sharing a similar common ligand site.