# An Investigation of Allostery in Epidermal Growth Factor Receptor Using Sextant with Dynamics Simulations to Expand an Apo Site

### Introduction

- Computational drug design typically requires a well-defined protein-ligand complex. Frequently, only _apo_ structures, which do not have bound ligands, are available. This limits exploration of druggable targets to sites that are open and relatively rigid in their _apo_ states.
- Here we explore a scenario where sequence-activity information has identified an allosteric site in the hinge region of EGFR (Fig. A). We use molecular dynamics to expand a pocket to grow small molecule binders in the _apo_ site.

### Method

- Interacting side chains are trimmed (key interactions with Lys52, Met73, Thr97, Phe163, Leu169)
- Sextant generates a small molecular probe in the site (Fig. B)
- Side chains returned, followed by 6 ns of dynamics simulation
- Process is repeated with larger molecular probe (Fig. B)
- QuADD generates candidates using final molecular probe as template

### Conclusions

- 15 of 346 **_QuADD_**-generated structures exactly reproduced the protein-ligand interactions (PLIFs) observed in the allosteric inhibitor and each exhibited greater ligand efficiencies (Figs. C & F)
- The **_QuADD_**  molecules have low structural similarity to the allosteric inhibitor ( _m.w._ 544, Fig. E)
- Using **_Sextant_** and **_QuADD_** in combination with dynamics simulations can enlarge an _apo_ binding site so that lead-like candidates can be generated in the site

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Authors: Petroff, Anna B.; Benson, Maurice; Byler, Kendall; Ingman, Victoria; Villar, Santiago; Hendrix, Paul; Simpson, William C.; Goldhagen, Guy; Shipman, William J.; Keinan, Shahar

Published On: February 28th, 2025