Abstract: Disclosed are substituted (4?-hydroxylphenyl)cycloalkane compounds and substituted (4?-hydroxylphenyl)cycloalkene compounds and there use as selective agonists of the estrogen receptor beta isoform (ER?). The disclosed compounds may be formulated as pharmaceutical compositions and administered for treating diseases associated with ER activity, such as neurological, psychiatric, and/or cell proliferative diseases and disorders as well as for enhancing memory consolidation in subjects in need thereof.

Abstract: Disclosed are substituted (4?-hydroxylphenyl)cycloalkane compounds and there use as selective agonists of the estrogen receptor beta isoform (ER?). The disclosed compounds may be formulated as pharmaceutical compositions and administered to treat diseases associated with ER activity, such as proliferative diseases and disorders and/or psychiatric diseases or disorders.

Abstract: Disclosed are substituted (4?-hydroxylphenyl)cycloalkane compounds and there use as selective agonists of the estrogen receptor beta isoform (ER?). The disclosed compounds may be formulated as pharmaceutical compositions and administered to treat diseases associated with ER activity, such as proliferative diseases and disorders and/or psychiatric diseases or disorders.

Abstract: Disclosed are dithio compounds that include a quenched fluorophore and a non-fluorophore peptide linked via a dithio bond to the fluorophore. The dithio compounds may be used in methods for detecting thiol-containing compounds or dithio-containing compounds. The dithio compounds also may be used as cellular probes where the peptide portion of the compounds targets the compounds to a specific cellular location.

Abstract: The invention provides a method for identifying a ligand that binds to a macromolecular target. The methods involve (a) attaching an antenna moiety to a first ligand, wherein the ligand binds specifically to a macromolecular target; (b) providing a sample comprising the macromolecular target, the first ligand and a candidate second ligand under conditions wherein the first ligand and the macromolecular target form a bound complex; (c) detecting a subset of magnetization transfer signals between the antenna moiety of the first ligand and the second candidate ligand, wherein the signals are obtained from an isotope edited NOESY spectrum of the sample; thereby determining that the two ligands are proximal in a bound complex, and identifying a second ligand that binds to the macromolecular target.

Abstract: The invention provides a method for identifying a ligand that binds to a macromolecular target. The methods involve (a) attaching an antenna moiety to a first ligand, wherein the ligand binds specifically to a macromolecular target; (b) providing a sample comprising the macromolecular target, the first ligand and a candidate second ligand under conditions wherein the first ligand and the macromolecular target form a bound complex; (c) detecting a subset of magnetization transfer signals between the antenna moiety of the first ligand and the second candidate ligand, wherein the signals are obtained from an isotope edited NOESY spectrum of the sample; thereby determining that the two ligands are proximal in a bound complex, and identifying a second ligand that binds to the macromolecular target.

Abstract: Disclosed are dithio compounds that include a quenched fluorophore and a non-fluorophore peptide linked via a dithio bond to the fluorophore. The dithio compounds may be used in methods for detecting thiol-containing compounds or dithio-containing compounds. The dithio compounds also may be used as cellular probes where the peptide portion of the compounds targets the compounds to a specific cellular location.

Abstract: Disclosed herein are methods related to drug development. The methods typically include steps whereby two chemical fragments are identified as binding to a target protein and subsequently the two chemical fragments are joined to create a new chemical entity that binds to the target protein.

Abstract: Disclosed herein are methods related to drug development. The methods typically include steps whereby an existing drug is modified to obtain a derivative form or whereby an analog of an existing drug is identified in order to obtain a new therapeutic agent that preferably has a higher efficacy and fewer side effects than the existing drug.

Abstract: Disclosed herein are dithio compounds that include at least one fluorophore. The compounds additionally may include a different fluorophore or a non-fluorophore. The dithio compounds may be used as reagents for detecting thiol-containing compounds.

Abstract: Disclosed are methods for detecting thiol-containing nucleotide diphosphates. The methods utilize thiol-reactive fluorescent reagents.

Abstract: The invention provides a method for obtaining a binding compound for a protein family, wherein the members of the protein family bind a common ligand. The method includes the steps of (a) providing a sample containing a protein from the protein family, a first ligand and a second ligand under conditions wherein the first ligand, the second ligand and the protein form a bound complex; (b) detecting magnetization transfer between the first ligand and the second ligand in the bound complex, thereby determining that the two ligands are proximal in the bound complex; and (c) obtaining a candidate binding compound including the first ligand, or a fragment thereof linked to the second ligand, or a homolog thereof, whereby the population contains binding compounds that bind to members of the protein family.

Abstract: Disclosed are methods for detecting thiol-containing nucleotide diphosphates. The methods utilize thiol-reactive fluorescent reagents.

Abstract: Disclosed are assays useful for detecting kinase activity. The assays utilize thiol-reactive fluorescent reagents and include reacting a reaction mixture that contains an ATP analog such as ATP?S to form an ADP analog such as ADP?S if kinase activity is present in the reaction mixture. The ADP analog reacts with the thiol-reactive fluorescent reagent and the reagent exhibits a change in fluorescence, thereby indicating that kinase activity is present in the reaction mixture.

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: 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: The invention provides methods for generating a library of bi-ligands, comprising (a) determining a common ligand to a conserved site in a receptor family; (b) attaching an expansion linker to the common ligand, wherein the expansion linker has sufficient length and orientation to direct a second ligand to a specificity site of a receptor in the receptor family, to form a module; and (c) generating a population of bi-ligands comprising a plurality of identical modules attached to variable second ligands. The invention also provides methods for identifying a bi-target ligand to a receptor by combining a first bi-ligand to a first receptor in a receptor family and a second bi-ligand to a second receptor in the receptor family. The invention additionally provides bi-ligands and bi-target ligands.

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 present invention provides common ligand mimics that act as common ligands for a receptor family. The present invention also provides bi-ligands containing these common ligand mimics. Bi-ligands of the invention provide enhanced affinity and/or selectivity of ligand binding to a receptor or receptor family through the synergistic action of the common ligand mimic and specificity ligand that compose the bi-ligand. The present invention also provides combinatorial libraries containing the common ligand mimics and bi-ligands of the invention. Further, the present invention provides methods for manufacturing the common ligand mimics and bi-ligands of the invention and methods for assaying the combinatorial libraries of the invention.

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.