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

> **NIH NIH R01** · TEXAS A&M AGRILIFE RESEARCH · 2024 · $116,586

## Abstract

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.

## Key facts

- **NIH application ID:** 11094570
- **Project number:** 3R01GM145751-03S1
- **Recipient organization:** TEXAS A&M AGRILIFE RESEARCH
- **Principal Investigator:** A. JOSHUA WAND
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $116,586
- **Award type:** 3
- **Project period:** 2022-09-20 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11094570

## Citation

> US National Institutes of Health, RePORTER application 11094570, Improving Fragment Based Drug Discovery and the Development of Tools for Chemical Biology through Nanoscale Encapsulation and NMR Spectroscopy (3R01GM145751-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11094570. Licensed CC0.

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