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

Abstract

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. 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.

Description

BACKGROUND 1. Technical Field This invention relates to computer assisted methods for identifying target binding sites on a molecule of interest and methods for designing ligands which bind to a molecule of interest. 2. Background Information Structure-based drug design is a major activity in pharmaceutical laboratories. The recent development of HIV-1 protease inhibitors is a major testimony to that effect. In structure-based drug design, the overall goal is to design a small molecule that binds to a specific site in a target molecule, usually a protein or other macromolecule. Where the target protein is an enzyme, the specific target site is often the substrate binding site or active site of the enzyme. Where the target protein is a receptor, the specific target site is often the binding site for a natural ligand of the receptor. In all cases the goal is to alter the behavior of the target molecule in a predetermined way as a result of the binding of the small molecule. The s...

AI Technical Summary

Benefits of technology

The invention features 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 and other macromolecules. The algorithm, referred to as “Woolford”, requires knowledge of the three-dimensional structure of the selected target protein or target macromolecule. However, Woolford does not require 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. In another aspect of the invention, once binding targets are identified, optimal ligands are designed and progressively built by the addition of individual atoms or amino acids in the csae of peptide design that complement structurally and energetically the selected target site.

Problems solved by technology

The situation is more complicated if the location of these sites is not known or if targeting a second binding site is required (a situation necessary, e.g., in cases where resistance towards an existing drug develops).

Furthermore, the optimization of lead compounds is a very demanding endeavor requiring the chemical synthesis and characterization of a very large number of derivatives.

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