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. 2016 Oct 10;22(42):14826-14830.
doi: 10.1002/chem.201603001. Epub 2016 Sep 7.

Fragment-Based Drug Design Facilitated by Protein-Templated Click Chemistry: Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin

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Free PMC article

Fragment-Based Drug Design Facilitated by Protein-Templated Click Chemistry: Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin

Milon Mondal et al. Chemistry. .
Free PMC article

Abstract

There is an urgent need for the development of efficient methodologies that accelerate drug discovery. We demonstrate that the strategic combination of fragment linking/optimization and protein-templated click chemistry is an efficient and powerful method that accelerates the hit-identification process for the aspartic protease endothiapepsin. The best binder, which inhibits endothiapepsin with an IC50 value of 43 μm, represents the first example of triazole-based inhibitors of endothiapepsin. Our strategy could find application on a whole range of drug targets.

Keywords: click chemistry; drug design; enzymes; inhibitors; liquid chromatography.

Figures

Figure 1
Figure 1
Schematic representation of protein‐templated click chemistry leading to a triazole‐based inhibitor starting from a library of azides and alkynes.
Figure 2
Figure 2
X‐ray crystal structure of endothiapepsin in complex with fragments 1 and 2 (PDB code: 3PBZ and 3PLD, respectively) and a modeled potential triazole inhibitor in the active site.36 Color code: protein skeleton: C: gray, O: red, and N: blue; fragment skeleton: C: purple, yellow and green, N: blue, O: red, Cl: green. Hydrogen bonds below 3.0 Å are shown as black, dashed lines.38
Scheme 1
Scheme 1
a) Structures and retrosynthetic analysis of the designed triazole inhibitors starting from fragments 1 and 2; b) structures of the azides 311 and the alkynes 1215.
Figure 3
Figure 3
Structure of the triazoles (1720) identified using PTCC, inactive triazole 21.
Figure 4
Figure 4
Moloc‐generated modeled structures of: a) 17, and b) (S)‐18 in the active site of endothiapepsin. Color code: inhibitor skeleton: C: green, violet, N: blue, O: red; enzyme skeleton: C: gray. H bonds below 3.2 Å are shown as black, dashed lines.

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