# Unusual Pharmacophores and New Tools for Cross-Coupling

> **NIH NIH R35** · SCRIPPS RESEARCH INSTITUTE, THE · 2024 · $249,850

## Abstract

Abstract of “Unusual Pharmacophores and New Tools For Cross-Coupling,” 5R35GM122606
 Bioassay-guided fractionation of cells uncovers small molecules that bind receptors in new and
unexpected ways. These cellular metabolites emerge from evolution with complex molecular features
preoptimized for function. High stereochemical content, high globularity and diverse heteroatom content
impart greater specificity of protein binding and greater aqueous solubility than simple, flat and non-polar
substances. Parametrization of large molecular libraries have supported a correlation between evolutionary
optimization and therapeutic design: “drug” chemical space is optimized away from commercial building
blocks and towards natural products (NP space). These types of molecules represent a challenge to chemical
synthesis, however, and require the development of new chemical tools for optimization and human use.
 This grant advances our work towards the rapid access and navigation of NP space. Our robust
routes to complex molecules have proven practical: synthesis allowed us to annotate and modify biological
function. Over the coming grant period we extend this approach into three areas. First, we develop the
chemistry to access two chemotypes with known phenotypic effects but unknown biological targets. One
target has stimulated the discovery of a new, stereoselective cross-coupling reaction, whereas another has
inspired the conversion of inert scaffolds to new warheads for protein adduction. Second, we describe rapid
access to complex ligands of known biological targets that embody ‘combinatorial’ aggregates of multiple
proteins. Diverse structural modifications of the complex small molecule will enable a search for selectivity
among these combinatorial targets with consequences for therapeutic development. Third, selectivity
defines the future goals of dual-catalytic cross-couplings to reach NP space: we seek to address substrate
selectivity, relative stereoselectivity and absolute stereoselectivity.

## Key facts

- **NIH application ID:** 11095683
- **Project number:** 3R35GM122606-08S1
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Ryan Ashok Shenvi
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,850
- **Award type:** 3
- **Project period:** 2017-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11095683

## Citation

> US National Institutes of Health, RePORTER application 11095683, Unusual Pharmacophores and New Tools for Cross-Coupling (3R35GM122606-08S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11095683. Licensed CC0.

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