# 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 · $298,400

## 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 “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.
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.
The door is now open to more fully realize the tremendous promise of FBDD but critical questions remain: 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 useful are the very weakly binding hits for lead development? Does the Ro5 library
offer a better compromise of hit 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:** 10911303
- **Project number:** 5R01GM145751-03
- **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:** $298,400
- **Award type:** 5
- **Project period:** 2022-09-20 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10911303

## Citation

> US National Institutes of Health, RePORTER application 10911303, Improving Fragment Based Drug Discovery and the Development of Tools for Chemical Biology through Nanoscale Encapsulation and NMR Spectroscopy (5R01GM145751-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10911303. Licensed CC0.

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