Abstract: The present invention provides compounds that efficiently and specifically inhibit lethal factor (LF) protease activity of anthrax toxin.

Abstract: The present disclosure provides compounds having the general structure A or pharmaceutically acceptable salts thereof: R—X??(A) wherein R is an alkyl or aryl moiety comprising heterocyclic structures; and X is a metal-chelatin group selected from: This disclosure further provides a focused library of compounds for use in the discovery and design of metallo-enzyme inhibitors. This fragment-based approach provides an assembly of a library of low molecular weight compounds (MW<300 Da) containing a variety of potential metal-chelating groups. The identification of the inhibitory scaffolds among these compounds provides the initial hit fragments that may be optimized for affinity against a particular target using common medicinal chemistry, structure-based or NMR-based approaches.

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: The invention provides compounds that can efficiently and specifically inhibit bacterial toxins, such as inhibit the lethal factor (LF) protease activity of anthrax toxin and/or botulinum neurotoxin type A. The invention also provides methods for inhibiting proteases, such as lethal factor protease, as well as methods for treating bacterial infections, such as anthrax and botulinum.

Abstract: The invention generally relates to compositions and methods for treatment of disease caused by Yersinia spp. infection. More specifically, the invention relates to protein tyrosine phosphatase inhibitors and derivatives and analogs thereof, pharmaceutical compositions containing the protein tyrosine phosphatase inhibitors and analogs, methods of making the protein tyrosine phosphatase inhibitors and analogs and methods of use thereof.

Abstract: A compound having the structure A is described as well as the use of such compounds to inhibit at least one BCL-2 protein family member.

Abstract: The present invention describes an improved method for screening compounds for activity in inhibiting the enzymatic activity of Akt1 protein kinase, also known as Protein Kinase B, an enzyme that is believed to play a key role in the inhibition of apoptosis and thus in the etiology of cancer and other conditions, including neurodegenerative diseases.

Abstract: Various compounds comprising a thiazolidine ring are described as well as the use of such compounds to inhibit at least one BCL-2 protein family member. One of the compounds described has the structure the structure A, wherein each of R1, and R2 comprises hydrogen, a substituted or unsubstituted straight-chained aliphatic group, a halogen, an alkoxyl, a halogen-substituted alkyl, a halogen-substituted alkoxyl, hydroxyl, carboxyl, cyano group, an amido group, a substituted or unsubstituted cycloaliphatic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heterocyclic group; X comprises oxygen, sulfur, or imino group; and Z comprises a moiety such as naphthaline or dehydronaphthaline, among others.

Abstract: The present invention provides compounds having the general structure I, or a pharmaceutically acceptable salt thereof: wherein X is a six-member ring selected from phenyl, pyridine, or pyrimidine; Y is H, an alkenyl, a substituted alkenyl, or alkynyl, and R is H or alkyl. Pharmaceutical compositions for treating various disorders such as cancers, the compositions including compound I are also provided.

Abstract: Methods of using apogossypol and its derivatives for treating inflammation is disclosed. Also, there is described a group of compounds having structure A, or a pharmaceutically acceptable salt, hydrate, N-oxide, or solvate thereof are provided: wherein each R is independently selected from the group consisting of H, C(O)X, C(O)NHX, NH(CO)X, SO2NHX, and NHSO2X, wherein X is selected from the group consisting of an alkyl, a substituted alkyl, an aryl, a substituted aryl, an alkylaryl, and a heterocycle. Compounds of group A may be used for treating various diseases or disorders, such as cancer.

Abstract: The present invention provides compound having the general structure A or pharmaceutically acceptable salts thereof: Het-L-P??(A) wherein Het is an aromatic moiety comprising a heterocyclic structure mimicking ATP, P is a docking site derived peptide or a docking site peptide mimetic, and L is a linking moiety, wherein L links the ATP mimetic to the docking site peptide moiety. The compounds having the general structure A can serve as inhibitors of kinases, such as the kinases JNK, Erk and p38.

Abstract: The present invention provides compounds having the general structure I, or a pharmaceutically acceptable salt thereof: wherein Z is selected from a group consisting of O, C, N, and S; each of Ar1, Ar2, and Ar3 is a moiety selected from a group consisting of an aryl and a substituted aryl; Y is selected from a group consisting of S, O, CH2 and SO2; K is selected from a group consisting CH2, CF2, O, NH, and SO2; each of n1 and n2 is an integer selected from a group consisting of 0, 1, 2, 3, and 4; and each of x, y, m1 and m2 is an integer selected from a group consisting of 0 and 1. Pharmaceutical compositions based on compounds I are also provided for treatment of a neurological disorders, diseases, or pathologies, and for treatment of infectious diseases.

Abstract: The present invention provides compounds that efficiently and specifically inhibit lethal factor (LF) protease activity of anthrax toxin.

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: Various phenylamine derivatives are described as well as the use of compounds to inhibit BID protein for controlling apoptotic cascade.

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: Methods of detecting interactions of a putative ligand with a selectively labeled target molecule, methods of screening for compounds which bind to a selectively labeled target molecule, methods for calculating the dissociation constant of a ligand that binds to a selectively labeled target molecule, and methods to determine the specific amino acids of a target molecule affected by the binding of a ligand, as well as compounds identified by these screening methods, are 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: The invention provides a method for determining a structure model for a test ligand bound to a macromolecule binding site. Structural constraints for the test ligand are derived from spectroscopic signals arising from interactions between the test ligand and macromolecule. The structure constraints are used as constraints in docking a structure model of the ligand to a structure model of the macromolecule, or as constraints in overlaying a structure model of the test ligand on the known structure for a reference ligand that binds to the macromolecule. The invention further provides a method for determining a structure model for a macromolecule bound to a ligand. Structural constraints derived from spectroscopically observed interactions of the macromolecule and a reference ligand are used to guide molecular modeling or to evaluate the results of a molecular modeling simulation of the macromolecule.