Peptidomimetic compounds and related methods
OwnerKevin Burgessinventor
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Abstract
Provided herein are compounds and methods of using same for the perturbation and/or inhibition of protein-protein interactions. Also provided herein is a data mining method useful for the identification of protein-protein interactions that may be inhibited by these compounds.
Claims36
A compound of formula (I):
- wherein R is selected from the group consisting of hydrogen, alkyl, heteroalkyl, and a nitrogen protecting group;
- R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl and alkyl-heterocycloalkyl;
- wherein each R1 and each R2 is optionally, independently substituted one or more times with substituents selected from oxo, carboxyl, carboxamide, carboxyalkyl, hydroxyl, alkoxy, amino, aminoalkyl, thio, thioalkyl and seleno;
- R3 is selected from the group consisting of hydrogen, alkyl, heteroalkyl and an oxygen protecting group;
- R4 is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl and heteroaryl;
- Each m is independently 1-2;
- Each n is independently 0-2;
- Each o is independently 1-2;
- a is 0-1;
- b is 1-3;
- and
- c is 0-1;
- wherein, when b is greater than 1, each R1 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl and alkyl-heterocycloalkyl, each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl and heteroaryl, and each n is independently 0-2.
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A method for selecting protein-protein interactions that may be perturbed by a molecule having two or more amino acid side-chains, comprising the steps of:
- (i) simulating one or more conformations of the molecule that have energies within 3 kcal/mol of the most stable conformer located in this simulation procedure.
- (ii) assigning three-dimensional coordinates to the Cα and Cβ atoms of the amino acid side chains in each conformation of (i);
- (iii) assigning three-dimensional coordinates to the Cα and Cβ atoms of the amino acid side chains in each member of a group of structurally characterized protein-protein interactions;
- (iv) overlaying the coordinates from (ii) on the coordinates from (iii) and measuring goodness-of-fit for each overlay
- (v) selecting those overlays from (iv) having a goodness-of-fit within a predetermined tolerance.
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An algorithm for matching side-chain orientations in protein-protein interactions, as shown by X-ray or NMR studies, with one or more preferred conformations of a compound that has similar side chains.
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Dependencies are inferred from the claim text.