# Targeting protein-protein interactions as drug targets

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $236,563

## Abstract

7. Project Summary. This proposal describes a program to identify drug targets for tuberculosis and
Escherichia coli infections through the combination of computational and experimental methods to elucidate
targets within mycobacterial and bacterial fatty acid synthesis. In Escherichia coli, the pathway involves 27
discrete interactions between AcpP and its partner proteins. In tuberculosis, the FAS-II pathway is involved the
production of mycolic acids, which serve a pivotal role in the virulence of Mycobacterium tuberculosis (Mtb). As
both pathways require an acyl carrier protein (ACP) to deliver growing fatty acyl substrates and intermediates
to associated partner proteins (PPs), protein-protein interactions within the AcpP.PP complex are an essential
for effective substrate processivity. Resolution of the structures of these assemblies and the interactions
responsible for their formation will not only further our knowledge of the mechanisms by which these proteins
function and are regulated but will also enable structure-based drug discovery work. In order to elucidate these
structures, we will leverage our knowledge of the Escherichia coli AcpP.PP interfaces to identify a
computational docking protocol that produces novel Mtb AcpP.PP structures. Our computational methodology
will be optimized by evaluating its effectiveness in recapitulating known structures of E. coli AcPP.PP
complexes resolved via NMR and X-ray crystallography studies. This computational protocol, once tested, will
be used to predict both AcpP.PP and AcpM.PP complexes. The structures of the resulting complexes will then
be validated using NMR titration and mutagenesis experiments. The resulting models will be refined using
molecular dynamics simulations, which yield a dynamical understanding protein structure that will inform
computer-aided drug discovery efforts.

## Key facts

- **NIH application ID:** 10110521
- **Project number:** 1R21AI156484-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Michael D. Burkart
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $236,563
- **Award type:** 1
- **Project period:** 2020-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10110521

## Citation

> US National Institutes of Health, RePORTER application 10110521, Targeting protein-protein interactions as drug targets (1R21AI156484-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10110521. Licensed CC0.

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