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Characterizing the Binding and Inhibition Mechanisms of Small Molecules Targeting Intrinsically Disordered Proteins

Award Number: R35GM142750
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Characterizing the Binding and Inhibition Mechanisms of Small Molecules Targeting Intrinsically Disordered Proteins - Project Summary /Abstract Intrinsically disordered proteins (IDPs), which lack a fixed three-dimensional structure under physiological conditions, represent approximately 40% of the human proteome. IDPs play essential roles in a wide range of biological processes and biomolecular assemblies and are implicated in numerous currently untreatable human diseases. Because IDPs exist as dynamic ensembles of rapidly interconverting conformations, they are not suitable targets for conventional structure-based drug discovery approaches. Expanding the druggable proteome to include IDPs could unlock therapeutic strategies for currently untreatable diseases. This research program integrates state-of-the-art all-atom molecular dynamics computer simulations with experimental data from nuclear magnetic resonance (NMR) spectroscopy and other biophysical methods to obtain atomic-resolution insights into the dynamic binding mechanisms of small molecules to IDPs. Previously, we characterized the binding mechanisms of the small molecule prostate cancer drug candidates that target the intrinsically disordered activation domain of the androgen receptor, facilitating the discovery of new inhibitors. Recent studies have provided strong evidence that the biological activity of some small molecule IDP inhibitors arises from their interactions with higher-order oligomeric assemblies of IDPs that act as intermediates in the formation of biomolecular condensates or amyloid fibrils. The mechanisms by which ligands engage with these dynamic and heterogeneous IDP assemblies remain poorly understood. Building on our previous progress, this proposed research will extend our integrative approach to characterize the interactions of small molecules with heterogeneous oligomeric assemblies of IDPs in atomic detail. Specifically, we will dissect the driving forces that confer ligand affinity to monomeric and multimeric androgen receptor species and use this information to design new inhibitors that modulate the conformational properties of the androgen receptor within biomolecular condensates and modulate the properties of transcriptional androgen receptor condensates in cells. We will extend our approach to determine how small molecules inhibit the aggregation of human islet amyloid polypeptide, a process associated with the onset of type 2 diabetes. To facilitate these efforts, we propose to develop new computational methods to improve the accuracy and efficiency of all-atom computer simulations of IDPs and IDP-ligand binding, and new approaches to guide inhibitor design and discovery. These studies will advance our mechanistic understanding of small-molecule binding to IDPs and establish general frameworks to support therapeutic development for diseases linked to IDP dysfunction, such as castration-resistant prostate cancer and type 2 diabetes.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $449,625 )
2026	2026	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	6	6/11/2026	COMPETING CONTINUATION	$449,625
														Subtotal = $449,625

Issue Date FY: 2025 ( Subtotal = $409,560 )
2025	2025	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	5	7/3/2025	NON-COMPETING CONTINUATION	$409,560
														Subtotal = $409,560

Issue Date FY: 2024 ( Subtotal = $409,560 )
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	4	6/12/2024	NON-COMPETING CONTINUATION	$409,560
														Subtotal = $409,560

Issue Date FY: 2023 ( Subtotal = $409,560 )
2023	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	3	5/30/2023	NON-COMPETING CONTINUATION	$409,560
														Subtotal = $409,560

Issue Date FY: 2022 ( Subtotal = $409,560 )
2022	2022	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	2	6/30/2022	NON-COMPETING CONTINUATION	$409,560
														Subtotal = $409,560

Issue Date FY: 2021 ( Subtotal = $341,681 )
2021	2021	TRUSTEES OF DARTMOUTH COLLEGE	6001 PARKHURST HALL STE 207	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	1	9/9/2021	NEW	$341,681
														Subtotal = $341,681

Grand Total All Awards = $2,429,546

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Characterizing the Binding and Inhibition Mechanisms of Small Molecules Targeting Intrinsically Disordered Proteins

Award Number: R35GM142750

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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