Johns Hopkins University

Avia Biosystems, LLC

Other

University of Pennsylvania

Columbia University

Dana-Farber-Cancer Institute Inc.

Unchained Labs

Bryn Mawr College

Fulcrum Pharmaceuticals Inc.

Ernesto Freire

Burleigh Hutchins

Richard Brown

Patrick C Ross

Irene Luque

Amos B Smith, Iii

Joseph G Sodroski

Joel R Courter

Wayne A Hendrickson

Navid Madani

Judith M LaLonde

Amy M Princiotto

Rogelio Siles

Vincent V Kavina

Arne Schön

Takahiro Soeta

Matthew Le-Khac

Peter L Privalov

George P Privalov

Peter D Kwong

John R Mascola

David Michael Jones

Raphael M Ottenbrite

Young Do Kwon

Yoshiaki Kiso

Xueling Wu

Danny Ng

Yingxin Xiao

Alexander W Sun

Toyoharu Kobayashi

Jongwoo Park

Azin Nezami

Matthew J Todd

The invention provides for compounds of formula I: wherein Z is absent or (CRR)W; 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, NHR, NRR, SH, S(O)R; or (iii) Rand Rtogether form C(O); W is absent, C(O), C(O)O, C(O)NRR, O, S(O), or NRR; Y is an optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted aryl, or NRR; wherein Rand Rare each independently H, alkyl or aryl; Xis selected from the group consisting of halogen, methyl, and hydroxyl; X2 is a halogen; each Ris 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. 

Small molecule CD4 mimetics and uses thereof

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

High affinity beta lactamase inhibitors

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.

System and method for pH formulations

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.

CD4-mimetic inhibitors of HIV-1 entry and methods of use thereof

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

Serine protease inhibitors

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.

Method for generation of automated denaturation graphs

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.

System and method to measure dissociation constants

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.

System for creation of formulations and generation of denaturation graphs

Compounds and methods for the inhibition of anti-malarial target aspartyl protease plasmepsins (e.g. Plasmepsin I, Plasmepsin II, Plasmepsin IV and HAP) are provided. The compounds are based on allophenylnorstatine substituted at positions R1-R4, such that R1 is isoquinoline, carboxyl, naphtalene, phenyl, phenol, benzene, an amino acid, and derivatives thereof; R2 and R3 are aliphatic groups; and R4 is indan, naphthalene, benzylamine, phenyl, phenol, cyclopentane, tert-butylamine, or derivatives thereof. The compounds may be used to inhibit Plasmepsin II, to kill malarial parasites, and to treat malaria in a patient. Certain of the substituted allophenylnorstatine-based compounds also exhibit inhibitory activity against Cathepsin D.

Inhibitors of plasmepsins

The invention provides novel non-&#x3b2;-lactam inhibitors of &#x3b2;-lactamases. In particular, the invention provides boronic acid-based compounds set forth in the specification. These compounds may be used with &#x3b2;-lactam antibiotics to bacterial infection, particularly, &#x3b2;-lactam-antibiotic-resistant bacterial infections. These compounds are also antibacterial agents by themselves. The invention further provides methods of using such compounds. Finally, the invention provides a pharmaceutical composition comprising these compounds.

&#x3b2;-lactamase inhibitors and methods of use thereof

The present invention provides a computer-assisted method for creating and displaying a model of a molecule in which residues that are affected by the binding of a ligand to the molecule are highlighted, making it possible to trace the path of propagation of a binding signal through the molecule. In order to carry out the method, the binding site determinants of the molecule are determined and the binding constant for the ligand is calculated. The states of a conformational ensemble that are binding competent are identified, and the Gibbs energy and probability of each state and the stability constant per residue of the molecule are calculated in the presence and absence of the ligand. Those residues that display a difference in stability constant in the presence vs absence of ligand are those which are affected by the binding of the ligand.

Structural prediction of allosterism

A computer-based method for the identification of binding targets in proteins and other macromolecules is provided. More particularly, the invention includes an algorithm aimed at predicting binding targets in proteins. This algorithm, named Woolford, requires knowledge of the high resolution structure of the protein but no knowledge of the location or identity of natural binding sites or ligands. Binding targets in the protein are identified and classified according to their expected optimal affinities. Binding targets can be located at the protein surface or at internal surfaces that become exposed as a result of partial unfolding, conformational changes, subunit dissociation, or other events. The entire protein is mapped according to the binding potential of its constituent atoms. Once binding targets are identified, optimal ligands are designed and progressively built by the addition of individual atoms or chemical groups that complement structurally and energetically the selected target. This algorithm is expected to have significant applications in structure-based drug design since it allows: 1) identification of binding targets in proteins; 2) identification of additional targets if the primary target is known; 3) design of ligand molecules with optimal binding affinities for the selected target; and 4) refinement of lead compounds by defining the location and nature of chemical groups for optimal binding affinity.

Method for prediction of binding targets and the design of ligands

The present invention provides a method of rapidly screening ligands on the basis of their binding affinity and binding enthalpy by carrying out binding assays at a minimum of two temperatures. This technique permits the selection for further optimization of lead ligands that bind to the target molecules with favorable enthalpies. Those ligands will exhibit higher solubilities in aqueous solution than ligands selected by conventional means, and may exhibit lower susceptibilities to resistant mutations. The method may be utilized as a standalone technique, or may be adapted to, for example, known high throughput screening technologies. The present invention further comprises an apparatus for carrying out the described methods.

Method for high throughput thermodynamic screening of ligands

A computer-based method for the identification of binding targets in proteins and other macromolecules. More particularly, the invention includes an algorithm aimed at predicting binding targets in proteins. This algorithm, named Woolford, requires knowledge of the high resolution structure of the protein but no knowledge of the location or identity of natural binding sites or ligands. Binding targets in the protein are identified and classified according to their expected optimal affinities. Binding targets can be located at the protein surface or at internal surfaces that become exposed as a result of partial unfolding, conformational changes, subunit dissociation, or other events. The entire protein is mapped according to the binding potential of its constituent atoms. Once binding targets are identified, optimal ligands are designed and progressively built by the addition of individual atoms that complement structurally and energetically the selected target.

Method for the prediction of binding targets and the design of ligands

A capillary calorimetric cell comprises a solid metallic block having a plurality of channels formed therein. Each channel has first and second ends opening to a first end face and a second end face, respectively, of the block. First and second members are disposed at the first and second end faces of the block, respectively, and cooperate with the block so that adjacent first ends and adjacent second ends of the channels are connected to thus form a single, continuous channel through the block.

Growing community of inventors

Baltimore, MD, United States of America

Ernesto Freire