Methods and systems for identifying compounds for forming, stabilizing or disrupting molecular complexes

A method for identifying one or more compounds that cause protein complex formation, stabilization, or dissociation, comprising:

• fractioning a first sample comprising a first portion of a biological sample comprising proteins, using size-exclusion chromatography to generate a first plurality of fractions;
• fractioning a second sample comprising (i) second portion of the biological sample and (ii) a compound library or a natural extract, using the size-exclusion chromatography to generate a second plurality of fractions;
• analyzing the first plurality of fractions and the second plurality of fractions to identify proteins in the first plurality of fractions and the second plurality of fractions;
• identifying, for a target protein, a fractionation shift between the first plurality of fractions and the second plurality of fractions, wherein the fraction shift indicates complex formation or stabilization, or complex dissociation, caused by one or more compounds in the compound library or the natural extract;
• and
• identifying the one or more compounds that cause the fraction shift, comprising analyzing (1) for a fraction shift indicating complex formation or stabilization caused by the one or more compounds, a fraction from the second plurality of fractions that comprises the target protein to identify one or more compounds in the fraction that co-elutes with the target protein, or (2) for a fraction shift indicating complex dissociation caused by the one or more compounds, (i) a fraction from the second plurality of fractions that comprises the target protein to identify one or more compounds in the fraction that co-elutes with the target protein, or (ii) a fraction from the second plurality of fractions that comprises a binding protein that forms a complex with the target protein in the absence of the one or more compounds to identify the one or more compounds in the fraction that co-elutes with the binding protein.

A system comprising:

• one or more processors;
• and
• a non-transitory computer readable storage medium storing one or more programs that, when executed by the one or more processors, cause the system to:
• receive a first proteomics profile data for a first plurality of fractions obtained by fractioning, using size-exclusion chromatography, a first sample comprising a portion of a biological sample comprising proteins;
• receive second proteomics profile data for a second plurality of fractions obtained by fractioning, using the size exclusion chromatography, a second sample comprising (i) second portion of the biological sample and (ii) a compound library, a drug, or a natural extract;
• identify, based on the first proteomics profile data and the second proteomics data, proteins in the first plurality of fractions and the second plurality of fractions;
• identify, for a target protein, a fractionation shift between the first plurality of fractions and the second plurality of fractions, wherein the fraction shift indicates complex formation or stabilization, or complex dissociation, caused by one or more compounds in the compound library, the drug, or the natural extract;
• and
• identify one or more binding proteins that form a complex with the target protein, wherein:
• co-elution of the one or more binding proteins with the target protein in the second plurality of fractions but not the first plurality of fractions indicates that a compound in the compound library, the drug, or the natural extract causes the formation or stabilization of a complex comprising the target protein and at least one of the one or more binding proteins;
• and
• co-elution of the one or more binding proteins with the target protein in the first plurality of fractions but not the second plurality of fractions indicates that a compound in the compound library, the drug, or the natural extract causes the dissociation of a complex comprising the target protein and at least one of the one or more binding proteins.

A system comprising:

• one or more processors;
• and
• a non-transitory computer readable storage medium storing one or more programs that, when executed by the one or more processors, cause the system to:
• receive a first proteomics profile data for a first plurality of fractions obtained by fractioning, using size-exclusion chromatography, a first sample comprising a portion of a biological sample comprising proteins;
• receive second proteomics profile data for a second plurality of fractions obtained by fractioning, using the size exclusion chromatography, a second sample comprising (i) second portion of the biological sample and (ii) a compound library or a natural extract;
• and
• identify, based on the first proteomics profile data and the second proteomics data, proteins in the first plurality of fractions and the second plurality of fractions;
• identify, for a target protein, a fractionation shift between the first plurality of fractions and the second plurality of fractions, wherein the fraction shift indicates complex formation or stabilization, or complex dissociation, caused by one or more compounds in the compound library or the natural extract;
• receive metabolomics data for the compound library or the natural extract;
• receive metabolomics data for a fraction, from the second plurality of fractions, comprising the target protein or a binding protein that forms a complex with the target protein in the absence of the one or more compounds;
• and
• identify the one or more compounds that cause the fraction shift by analyzing the metabolomics data for the compound library or the natural extract and the metabolomics data for the fraction, from the second plurality of fractions, comprising the target protein or the binding protein that forms a complex with the target protein in the absence of the one or more compounds.