Method to design therapeutically important compounds
AssigneeWisconsin Alumni Research Foundation
InventorsMatthew G. Bursavich, Daniel H. Rich
Life of this patent
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Abstract
Disclosed is are methods of generating chemical structures of putative non-peptide inhibitors of biologically-active receptors. The method includes constructing a model of a receptor-ligand complex using empirical three-dimensional data of the receptor-ligand complex. The conformation of the binding site between the receptor and the ligand is then altered to yield novel conformations not exhibited in either the native receptor or the bound receptor. These conformations are then used to generate models of non-peptide chemical structures that are complementary in structure to the altered conformations of the binding site. In this fashion, chemical structures of putative non-peptide inhibitors of the altered conformation are revealed.
Claims25
A method of generating chemical structures of putative non-peptide inhibitors of a biologically-active receptor, the method comprising:
- (a) constructing a model of a receptor-ligand complex using empirical three-dimensional data of the receptor-ligand complex, the model including a receptor portion and a ligand portion, whereby a conformation of a binding site between the receptor portion of the model and the ligand portion of the model is revealed;
- then
- (b) altering the conformation of the binding site of step (a) to yield a model of an altered conformation of the binding site;
- and then
- (c) generating models of non-peptide chemical structures that are complementary in structure to the altered conformation of the binding site from step (b), whereby chemical structures of putative non-peptide inhibitors of the altered conformation are revealed.
A method of generating, in silico, chemical structures of putative non-peptide inhibitors of a biologically-active receptor, the method comprising:
- (a) obtaining empirical three-dimensional data of the receptor bonded to a proteinaceous or non-proteinaceous ligand, the receptor and the ligand bonded thereto collectively referred to as a receptor-ligand complex;
- then
- (b) constructing a model of the receptor-ligand complex in silico using the data from step (a);
- then
- (c) excising the ligand from the model of the receptor-ligand complex of step (b), thereby yielding an in silico model of a conformation of a binding site on the receptor;
- then
- (d) altering the model of the conformation of the binding site of step (c) to yield a model of an altered conformation of the binding site;
- and then
- (e) generating, in silico, models of non-peptide chemical structures that are complementary in structure to the altered conformation of the binding site from step (d), whereby structures of putative non-peptide inhibitors of the altered conformation are revealed.
A method of generating chemical structures of putative non-peptide inhibitors of a biologically-active receptor, the method comprising:
- (a) obtaining three-dimensional data of the receptor bonded to a proteinaceous or non-proteinaceous ligand, the receptor and the ligand bonded thereto collectively referred to as a receptor-ligand complex;
- then
- (b) constructing a model of the receptor-ligand complex in silico using the data from step (a), thereby yielding an in silico model of a conformation of a binding site on the receptor when the binding site is occupied by the ligand;
- then
- (c) minimizing the model of the conformation of the binding site from step (d) to identify residues within the binding site that are mobile and proximal to the ligand, thereby yielding a minimized conformation model;
- then
- (d) generating, in silico, models of non-peptide chemical structures that are complementary in structure to the minimized conformation model of step (c), whereby structures of putative non-peptide inhibitors of the minimized conformation model are revealed.
A method of generating, in silico, chemical structures of putative non-peptide inhibitors of biologically-active receptors, the method comprising:
- (a) obtaining three-dimensional data of a receptor-ligand complex, the complex comprising a receptor bound to a protein or a non-protein ligand;
- and
- (b) constructing a model of the receptor-ligand complex in silico, thereby generating a first in silico model of a binding site conformation in the receptor-ligand complex;
- and then
- (c) in the model of step (b), mathematically overlapping in silico models of potential ligand inhibitors, the potential ligand inhibitors having chemical moieties that are proximal to mobile binding site residues in the receptor, thereby generating a second in silico model of a binding site conformation in the receptor-ligand complex;
- then
- (d) minimizing the model of step (c) to reveal novel binding conformations of the binding site residues in the receptor;
- and then
- (e) generating, in silico, models of non-peptide structures that are complementary to the novel binding conformations of the binding site residues from step (d).
Dependencies are inferred from the claim text.