Methods for identifying inhibitors of amyloid protein aggregation
Inventors
Barden, Christopher J. • Carter, Michael D. • Weaver, Donald F.
Assignees
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Publication Number
US-11568956-B2
Publication Date
2023-01-31
Expiration Date
Abstract
Methods for identifying compounds that are inhibitors or are likely to be inhibitors of amyloid protein aggregation, as well as three-dimensional, non-crystallographic models (i.e. “pseudo-crystal structures”) of amyloid aggregation utilized in the methods, are described. Means for creating the three-dimensional, non-crystallographic models (i.e. “pseudo-crystal structures”) of amyloid aggregation are also described.
Core Innovation
The invention provides a computer molecular modeling program on a computer system for identifying compounds that modulate amyloid aggregation. The method constructs a non-crystallographic three-dimensional model of a monomeric amyloid peptide and a three-dimensional model of an amyloid protein, positioned with respect to the amyloid peptide model so that a pocket is formed between the models for inserting a candidate compound.
Candidate compounds are selected, constructed in the computer molecular modeling program, docked into the pocket, and scored to reflect complementarity with respect to the pocket. The determined degree of complementarity is used to determine whether the candidate compound is capable of modulating amyloid aggregation, and compounds capable of modulating amyloid aggregation are output for further evaluation experimentally as amyloid aggregation inhibitors.
The amyloid peptide model is substantially SEQ ID: 1 and the amyloid protein model is substantially SEQ ID: 2, positioned substantially in the orientation shown in FIG. 2. Specific interactions are defined between Val at position 8 of SEQ ID: 1 and Glu at position 6 of SEQ ID: 2, Gly at position 9 of SEQ ID: 1 and Glu at position 6 of SEQ ID: 2, Ser at position 10 of SEQ ID: 1 and Gly at position 9 of SEQ ID: 2, Ser at position 10 of SEQ ID: 1 and Ser at position 10 of SEQ ID: 2, and Lys at position 12 of SEQ ID: 1 and Glu at position 6 of SEQ ID: 2.
Claims Coverage
The provided material contains three independent claims directed to a computer-based workflow for identifying compounds that modulate amyloid aggregation, with five inventive features centered on pocket formation, docking and scoring, complementarity-based selection, score-cutoff distinction, and sequence-defined interaction constraints.
Pocket-forming amyloid models defined by SEQ ID interactions
Constructing a non-crystallographic model of amyloid protein aggregation comprising a three-dimensional model of a monomeric amyloid peptide and a three-dimensional model of an amyloid protein positioned with respect to the amyloid peptide model such that a pocket is formed between the models, with the amyloid peptide model substantially SEQ ID: 1 and the amyloid protein model substantially SEQ ID: 2, positioned substantially in the orientation shown in FIG. 2 and defined by Val8/Glu6, Gly9/Glu6, Ser10/Gly9, Ser10/Ser10, and Lys12/Glu6 interactions.
Docking and complementarity scoring
Selecting a list of candidate compounds, constructing the candidate compounds in a computer molecular modeling program, docking each candidate compound into the pocket, and scoring each candidate compound to reflect complementarity with respect to the pocket, or determining degree of complementarity.
Complementarity-based identification of amyloid aggregation modulators
Using the determined degree of complementarity with respect to the pocket to determine whether the candidate compound is capable of modulating amyloid aggregation, and outputting compounds capable of modulating amyloid aggregation for further evaluation experimentally as amyloid aggregation inhibitors.
Score cutoff distinguishing active from inactive compounds
Identifying compounds that modulate amyloid aggregation or better modulate amyloid aggregation by reference to a score cutoff that reflects complementarity with respect to the pocket and substantially distinguishes active compounds from inactive compounds, or more active compounds from less active compounds.
Sequence-defined interaction constraints
The model and docking feature specified interactions between Val at position 8 of SEQ ID: 1 and Glu at position 6 of SEQ ID: 2, Gly at position 9 of SEQ ID: 1 and Glu at position 6 of SEQ ID: 2, Ser at position 10 of SEQ ID: 1 and Gly at position 9 of SEQ ID: 2, Ser at position 10 of SEQ ID: 1 and Ser at position 10 of SEQ ID: 2, and Lys at position 12 of SEQ ID: 1 and Glu at position 6 of SEQ ID: 2.
The claim scope centers on constructing non-crystallographic three-dimensional amyloid models to form a pocket, docking candidate compounds into that pocket and determining complementarity, and using complementarity and score cutoff to identify compounds capable of modulating amyloid aggregation for experimental evaluation, with sequence-defined interaction constraints.
Stated Advantages
Enables identification of compounds that modulate amyloid aggregation using a computer molecular modeling program.
Substantially distinguishes active compounds from inactive compounds by reference to a score cutoff based on complementarity with respect to the pocket.
Outputs active compounds for further evaluation experimentally as amyloid aggregation inhibitors.
Documented Applications
Using the computer molecular modeling program to identify compounds that modulate amyloid aggregation and output compounds for further experimental evaluation as amyloid aggregation inhibitors.
Identifying compounds as amyloid aggregation inhibitors to modulate amyloid aggregation.
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