Abstract: The present invention relates to, among other things, methods and systems for recognizing and characterizing protein aggregation processes at the earliest possible time and use of such new methods and systems for (1) the identification and selection of protein formulations that minimize aggregation and extend long-term stability and (2) the identification of protein variants with the lowest tendency to aggregate.

Abstract: A method includes receiving a sample. The method also includes applying a denaturing agent to a first portion of the sample, and detecting, in response to the application of the denaturing agent, a first measure from the first portion of the sample. The method also includes modifying the temperature of a second portion of the sample and detecting, in response to the modifying the temperature of the second portion of the sample, a second measure from the second portion of the sample. The method also includes computing thermodynamic information for the sample based on the indication of the first measure, and computing kinetic information for the sample based on the indication of the second measure. The method also includes computing, based on the thermodynamic information and the kinetic information, an indication of temporal stability of the protein component of the sample.

Abstract: The invention provides for compounds of formula I: wherein Z is absent or (CRARB)nW; each RA and RB is independently (i) H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, haloalkyl, each of which may be optionally substituted; (ii) OH, ORc, NH2, NHRc, NRcRc, SH, S(O)mRc; or (iii) RA and RB together form C(O); W is absent, C(O), C(O)O, C(O)NRcRc, O, S(O)m, or NRcRc; Y is an optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted aryl, or NRXRY; wherein Rx and Ry are each independently H, alkyl or aryl; X1 is selected from the group consisting of halogen, methyl, and hydroxyl; X2 is a halogen; each Rc is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which may be optionally substituted; m is O, 1, or 2; and n is 1, 2, 3, 4, 5, or 6; and pharmaceutically acceptable salts thereof.

Abstract: Inhibitors of beta lactamases and their use in treating bacterial infections are disclosed.

Abstract: A MEMS cassette for insertion into a DSC calorimeter and a DSC calorimeter using MEMS cassettes to conduct DSC experiments. The MEMS cassette includes a chip configured to conduct DSC reactions of a sample and reference to derive information regarding the sample.

Abstract: A system and method for creating a buffer solution having a desired pH value is disclosed. The method uses two known buffer solutions, each with predetermined pH values, and determines a mathematical relationship which defines the amount of each known buffer solution needed to create the buffer solution with the desired pH. This method can then be used to create one or more denaturation graphs, which demonstrate the stability of a protein at a given pH level.

Abstract: Described herein are methods of generating a protein binding domain that specifically binds to gp120 in a specific conformational state, comprising contacting gp120 with a CD4-mimetic compound, thereby forming gp120 in the specific conformational state; and generating antibodies to gp120 in the specific conformation state. Relatedly, the disclosure also describes methods of neutralizing HIV-1, comprising contacting HIV-1 with an effective amount of a CD4-mimetic compound, thereby forming HIV-1 having gp120 in a specific conformational state; and contacting the HIV-1 in the specific conformational state with an antibody.

Abstract: Described herein are small-molecule mimics of CD4, which both enter the Phe43 cavity and target Asp368 of gp120, the HIV-1 envelope protein. Also described herein are methods of using these compounds to inhibit the transmission or progression of HIV infection. These compounds exhibit antiviral potency greater than that of a known antiviral, NBD-556, with 100% breadth against clade B and C viruses. Importantly, the compounds do not activate HIV infection of CD4-negative, CCR5-positive cells, in contrast to NBD-556.

Abstract: Potent low molecular weight, highly selective, competitive non-peptidic serine protease inhibitors and their use in treating serine protease-associated diseases are disclosed.

Abstract: The present invention relates to, among other things, methods and systems for recognizing and characterizing protein aggregation processes at the earliest possible time and use of such new methods and systems for (1) the identification and selection of protein formulations that minimize aggregation and extend long-term stability and (2) the identification of protein variants with the lowest tendency to aggregate.

Abstract: A system and method for creating a buffer solution having a desired pH value is disclosed. The method uses two known buffer solutions, each with predetermined pH values, and determines a mathematical relationship which defines the amount of each known buffer solution needed to create the buffer solution with the desired pH. This method can then be used to create one or more denaturation graphs, which demonstrate the stability of a protein at a given pH level.

Abstract: A system and method for creating a plurality of denaturation curves is disclosed. In accordance with certain embodiments, one variable, such as salt content, pH or another parameter, is varied to create a plurality of different buffer solutions. Each is then used to create a denaturation graph. The plurality of denaturation graphs allows analysis of the effect of that variable on protein stability.

Abstract: Potent low molecular weight, highly selective, competitive non-peptidic serine protease inhibitors and their use in treating serine protease-associated diseases are disclosed.

Abstract: A system and method for determining the dissociation constant for a particular ligand is disclosed. In accordance with certain embodiments, the method creates a chemical denaturation curve of a protein in the absence of the ligand. A particular point is selected from this curve, such as the point at which 90% of the protein is unfolded. The molarity of chemical denaturant is determined for this selected point. A one point test is then performed for the protein with a predetermined concentration of the particular ligand. The fraction of protein which is unfolded at this point is then used to determine the dissociation constant for the ligand. This constant is used to quickly determine whether a particular ligard is well suited to be considered a potential drug candidate against that protein target.

Abstract: Inhibitors of beta lactamases and their use in treating bacterial infections are disclosed.

Abstract: A system for automatically creating a denaturation curve is disclosed. In accordance with certain embodiments, a movement system including a unit having a plurality of cannulas is used. The cannulas are in fluid communication with a fluid system, which allows the cannulas to draw in and dispense fluid. A measurement system is included which draws fluid from a well into a detector to determine a characteristic of the fluid. A controller is used to control these systems and also to create a denaturation graph from the measured characteristics. In another embodiment, a plurality of formulations may be created using the system.

Abstract: The invention provides for compounds of formula I: wherein Z is absent or (CRARB)nW; each RA and RB is independently (i) H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, haloalkyl, each of which may be optionally substituted; (ii) OH, ORc, NH2, NHL, NRcRc, SH, S(O)mRc; or (iii) RA and RB together form C(O); W is absent, C(O), C(O)O, C(O)NRcRc, O, S(O)m, or NRcRc; Y is an optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted aryl, or NRXRY; wherein Rx and Ry are each independently H, alkyl or aryl; X1 is selected from the group consisting of halogen, methyl, and hydroxyl; X2 is a halogen; each Rc is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which may be optionally substituted; m is O, 1, or 2; and n is 1, 2, 3, 4, 5, or 6; and pharmaceutically acceptable salts thereof.

Abstract: A system and method for creating a buffer solution having a desired pH value is disclosed. The method uses two known buffer solutions, each with predetermined pH values, and determines a mathematical relationship which defines the amount of each known buffer solution needed to create the buffer solution with the desired pH. This method can then be used to create one or more denaturation graphs, which demonstrate the stability of a protein at a given pH level.

Abstract: A system for automatically creating a denaturation curve is disclosed. In accordance with certain embodiments, a movement system including a unit having a plurality of cannulas is used. The cannulas are in fluid communication with a fluid system, which allows the cannulas to draw in and dispense fluid. A measurement system is included which draws fluid from a well into a detector to determine a characteristic of the fluid. A controller is used to control these systems and also to create a denaturation graph from the measured characteristics. In another embodiment, a plurality of formulations may be created using the system.

Abstract: A system and method for determining the dissociation constant for a particular ligand is disclosed. In accordance with certain embodiments, the method creates a chemical denaturation curve of a protein in the absence of the ligand. A particular point is selected from this curve, such as the point at which 90% of the protein is unfolded. The molarity of chemical denaturant is determined for this selected point. A one point test is then performed for the protein with a predetermined concentration of the particular ligand. The fraction of protein which is unfolded at this point is then used to determine the dissociation constant for the ligand. This constant is used to quickly determine whether a particular ligard is well suited to be considered a potential drug candidate against that protein target.