6UQD

Co-complex of S. pyogenes 10782 streptopain bound with a SuFEx-based optimized small molecule inhibitor

Summary for 6UQD

• Entry DOI: 10.2210/pdb6uqd/pdb
• Descriptor: Streptopain, benzyl [(1S)-2-(3-{[(4-carbamoylpiperidin-1-yl)(fluoro)oxo-lambda~6~-sulfanylidene]amino}phenyl)-1-cyanoethyl]carbamate (3 entities in total)
• Functional Keywords: speb, streptopain, inhibitor, nitrile, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Streptococcus pyogenes
• Total number of polymer chains: 2
• Total formula weight: 84078.98

Authors

Wolan, D.W.,Woehl, J.L.,Kitamura, S. (deposition date: 2019-10-18, release date: 2020-08-26, Last modification date: 2023-10-11)

Primary citation

Kitamura, S.,Zheng, Q.,Woehl, J.L.,Solania, A.,Chen, E.,Dillon, N.,Hull, M.V.,Kotaniguchi, M.,Cappiello, J.R.,Kitamura, S.,Nizet, V.,Sharpless, K.B.,Wolan, D.W.
Sulfur(VI) Fluoride Exchange (SuFEx)-Enabled High-Throughput Medicinal Chemistry.
J.Am.Chem.Soc., 142:10899-10904, 2020

PubMed Abstract: Optimization of small-molecule probes or drugs is a synthetically lengthy, challenging, and resource-intensive process. Lack of automation and reliance on skilled medicinal chemists is cumbersome in both academic and industrial settings. Here, we demonstrate a high-throughput hit-to-lead process based on the biocompatible sulfur(VI) fluoride exchange (SuFEx) click chemistry. A high-throughput screening hit benzyl (cyanomethyl)carbamate ( = 8 μM) against a bacterial cysteine protease SpeB was modified with a SuFExable iminosulfur oxydifluoride [RN═S(O)F] motif, rapidly diversified into 460 analogs in overnight reactions, and the products were directly screened to yield drug-like inhibitors with 480-fold higher potency ( = 18 nM). We showed that the improved molecule is active in a bacteria-host coculture. Since this SuFEx linkage reaction succeeds on picomole scale for direct screening, we anticipate our methodology can accelerate the development of robust biological probes and drug candidates.

PubMed: 32479075
DOI: 10.1021/jacs.9b13652

Experimental method

X-RAY DIFFRACTION (2.02 Å)