NMR data driven-HADDOCK docking model of PaDsbA—Fragment 1 complex.

<p><b>(A)</b> Overlay of the two hundred best scoring HADDOCK model structures after water refinement showing the conformation of Fragment <b>1</b> in the complex. <b>(B)</b> The lowest energy conformer from the HADDOCK calculation is shown as a representative model of the PaDsbA—Fragment <b>1</b> complex. PaDsbA1 is shown in cartoon. Methyl containing residues for which intermolecular NOEs were detected, are shown in blue-white sticks. Val19 and Val21 methyls are present in close proximity of the Fragment <b>1</b> binding site (shown in magenta sticks), however no NOE cross peaks were observed from these methyls to ligand protons.</p

NMR data driven HADDOCK docking model and X-ray crystal structure of PaDsbA1–Fragment 1 complex.

<p>The representative HADDOCK model and the crystal structure are shown in cartoon representation coloured green and magenta, respectively. The binding mode of Fragment <b>1</b> (shown as sticks) is similar in both models.</p

X-ray crystal structure of PaDsbA1-Fragment 1 complex.

<p>The structure of PaDsbA1 in complex with Fragment <b>1</b> was solved by X-ray crystallography. <b>(A)</b> Residues from both the helical (H2, H6) and TRX (B2, B1-B2, H6) domains contribute to the binding of Fragment <b>1</b>. Selected side chains, which make contact with Fragment <b>1</b> are shown as sticks, and hydrogen bonds identified in the complex as dashed black lines. <b>(B)</b> 2Fo-Fc (blue) electron density map for Fragment <b>1</b>, was generated from a simulated annealing omit map and is shown contoured at 1.0 σ. The maps are shown within a 2 Å radius of each atom of Fragment <b>1</b>. <b>(C)</b> Stereo representation highlighting the subset of side chain residues involved in either hydrogen bond or hydrophobic contacts with Fragment <b>1</b> in the complex. Hydrogen bonds are shown as black dashed lines.</p

Validated fragment hits with K_D values < 5 mM.

<p>Validated fragment hits with K_D values < 5 mM.</p

Structural statistics for the bundle of 20 energy-minimized NMR conformers of apo oxidised PaDsbA1 (3–192).

<p>Structural statistics for the bundle of 20 energy-minimized NMR conformers of apo oxidised PaDsbA1 (3–192).</p

Assignment of methyl resonances of oxidized PaDsbA1 in the presence of Fragment 1.

<p><b>(A)</b> Overlay of the methyl region of the ¹³C-HSQC spectra of PaDsbA1 in the absence (blue) and presence (red) of Fragment <b>1</b>. A subset of residues undergoes significant chemical shift perturbations. <b>(B)</b> Overlay of the ¹³C-HSQC spectra of PaDsbA1 in the absence (blue) and presence increasing concentrations of Fragment <b>1</b> (0.2–3.3 mM). Selected methyl resonance assignments are shown. The resonances for Leu63 and Leu144 undergo the largest chemical shift perturbations as indicated by arrows.</p

X-ray crystal structure of PaDsbA1 and Fragment 1: Refinement and model quality.

<p>X-ray crystal structure of PaDsbA1 and Fragment 1: Refinement and model quality.</p

Chemical shift perturbations are observed for residues on both the catalytic and non-catalytic face of oxidised PaDsbA1.

<p>Chemical shift perturbations observed in HSQC spectra of PaDsbA1 in the presence of 3.3 mM (A) Fragment <b>1</b>, <b>(B)</b> Fragment <b>2</b> and <b>(C)</b> Fragment <b>3</b>. CSP are plotted versus residue number. (<b>D-F</b>) In each case the chemical shift perturbations have been mapped onto the crystal structure of PaDsbA1 (PDB code: 3H93): minimum = 0.01 ppm (white) and maximum = 0.1 ppm (red). Shown are views of the catalytic face of PaDsbA1 (left) and the non-catalytic face (right). In each case there is a continuous cluster of chemical shift perturbations observed on the non-catalytic face. The unassigned active site histidine residue (His39) is highlighted in yellow.</p

An Orally Available 3-Ethoxybenzisoxazole Capsid Binder with Clinical Activity against Human Rhinovirus

Respiratory infections caused by human rhinovirus are responsible for severe exacerbations of underlying clinical conditions such as asthma in addition to their economic cost in terms of lost working days due to illness. While several antiviral compounds for treating rhinoviral infections have been discovered, none have succeeded, to date, in reaching approval for clinical use. We have developed a potent, orally available rhinovirus inhibitor <b>6</b> that has progressed through early clinical trials. The compound shows favorable pharmacokinetic and activity profiles and has a confirmed mechanism of action through crystallographic studies of a rhinovirus−compound complex. The compound has now progressed to phase IIb clinical studies of its effect on natural rhinovirus infection in humans

An Orally Available 3-Ethoxybenzisoxazole Capsid Binder with Clinical Activity against Human Rhinovirus

Respiratory infections caused by human rhinovirus are responsible for severe exacerbations of underlying clinical conditions such as asthma in addition to their economic cost in terms of lost working days due to illness. While several antiviral compounds for treating rhinoviral infections have been discovered, none have succeeded, to date, in reaching approval for clinical use. We have developed a potent, orally available rhinovirus inhibitor <b>6</b> that has progressed through early clinical trials. The compound shows favorable pharmacokinetic and activity profiles and has a confirmed mechanism of action through crystallographic studies of a rhinovirus−compound complex. The compound has now progressed to phase IIb clinical studies of its effect on natural rhinovirus infection in humans