Johns Hopkins University

Fulcrum Pharmaceuticals Inc.

Irene Luque

Ernesto Freire

Raphael M Ottenbrite

Patrick C Ross

Yingxin Xiao

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

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

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.

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Granada, Spain

Irene Luque