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Improving Fragment Based Drug Discovery and the Development of Tools for Chemical Biology through Nanoscale Encapsulation and NMR Spectroscopy

Award Number: R01GM145751
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Despite tremendous technical advances in drug discovery, de novo development of small molecule drugs is still challenging. High-throughput screening (HTS) with libraries of natural products and other complex molecules remains the bedrock approach. However, HTS is unsatisfactory in many ways: extraordinary cost, poor efficiency, rampant false positives and a complexity of discovered “hits” that hinders hit-to-lead development. Fragment based drug discovery (FBDD) was brilliantly conceived to overcome these limitations, but has arguably not performed as hoped. The limited impact of FBDD is because most fragment “hit” molecules are very weak binders and are undetectable by current assay methods. The enormous potential of FBDD is therefore lost. Here, an approach is to be developed that can reliably detect weak but specific binding with the goal of helping to reinvigorate and enhance early phase small molecule drug discovery. With a foundational premise of FBDD method thereby actually ensured, the full potential of the FBDD approach can be realized. Faithful detection of binding requires that the ligand and protein concentrations be at least on the order of the dissociation constant, which is practically and financially unrealistic for weak binders. The strategy to remove this basic barrier is simple. The water core of the reverse micelle (RM) is used to confine a single protein molecule and fragments at high enough concentrations to overcome the unfavorable binding entropy. NMR spectroscopy then permits site-resolved detection and quantification of binding affinity at reasonable cost. The first application of RM NMR FBDD highlights its potential to greatly expand small drug discovery. A rule-of-three (Ro3) fragment screen of interleukin-1β (IL-1β) shows that 1) weak yet specific binding can be efficiently detected in a structural context; 2) achieving the required high protein and ligand concentrations is economically feasible; 3) a high hit rate is observed; 4) surface coverage is extraordinary and gives unprecedented connectivity potential; 5) highly desired more polar binders are illuminated. Critical questions to be answered include: Is the IL-1β surface coverage typical? What is the distribution of fragment hit affinities of Ro3 and rule-of-five (Ro5) libraries more generally? What are the chemical characteristics of useful fragments to choose for an optimal RM NMR screening library? How difficult is to move weakly binding hits to the traditional hit-to-lead pipeline? Is the Ro5 library a better compromise of affinity and surface coverage? What is the most efficient way to carry out RM NMR screening? Is RM NMR screening quantitatively reliable? This project will address these and other technical challenges that stand in the way of creating a strategy that more fully enables the brilliant insights of the FBDD paradigm and unleashes its originally anticipated potential.


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: 2024 ( Subtotal = $414,986 )
2024	2024	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	001	3	9/12/2024	SUPPLEMENT FOR EXPANSION	$116,586
2024	2024	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	3	9/9/2024	NON-COMPETING CONTINUATION	$298,400
														Subtotal = $414,986

Issue Date FY: 2023 ( Subtotal = $298,442 )
2023	2023	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	2	8/21/2023	NON-COMPETING CONTINUATION	$298,442
														Subtotal = $298,442

Issue Date FY: 2022 ( Subtotal = $298,659 )
2022	2022	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	1	9/21/2022	NEW	$298,659
														Subtotal = $298,659

Grand Total All Awards = $1,012,087

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Improving Fragment Based Drug Discovery and the Development of Tools for Chemical Biology through Nanoscale Encapsulation and NMR Spectroscopy

Award Number: R01GM145751

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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