6MO5

Co-Crystal structure of P. aeruginosa LpxC-50228 complex

6MO5 の概要

• エントリーDOI: 10.2210/pdb6mo5/pdb
• 分子名称: UDP-3-O-acyl-N-acetylglucosamine deacetylase, N-[(2S)-1-(hydroxyamino)-3-methyl-3-{[(oxetan-3-yl)methyl]sulfonyl}-1-oxobutan-2-yl]-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: hydrolase lpxc pseudomonas aeruginosa, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34229.05

構造登録者

Stein, A.J.,Holt, M.C.,Assar, Z.,Cohen, F.,Andrews, L.,Cirz, R. (登録日: 2018-10-04, 公開日: 2019-07-17, 最終更新日: 2024-03-13)

主引用文献

Cohen, F.,Aggen, J.B.,Andrews, L.D.,Assar, Z.,Boggs, J.,Choi, T.,Dozzo, P.,Easterday, A.N.,Haglund, C.M.,Hildebrandt, D.J.,Holt, M.C.,Joly, K.,Jubb, A.,Kamal, Z.,Kane, T.R.,Konradi, A.W.,Krause, K.M.,Linsell, M.S.,Machajewski, T.D.,Miroshnikova, O.,Moser, H.E.,Nieto, V.,Phan, T.,Plato, C.,Serio, A.W.,Seroogy, J.,Shakhmin, A.,Stein, A.J.,Sun, A.D.,Sviridov, S.,Wang, Z.,Wlasichuk, K.,Yang, W.,Zhou, X.,Zhu, H.,Cirz, R.T.
Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety.
Chemmedchem, 14:1560-1572, 2019

PubMed Abstract: UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a Zn deacetylase that is essential for the survival of most pathogenic Gram-negative bacteria. ACHN-975 (N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose-limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN-975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC-516, (S)-N-(2-(hydroxyamino)-1-(3-methoxy-1,1-dioxidothietan-3-yl)-2-oxoethyl)-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30 mg mL for parenteral administration and conversion into the active drug with a t of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.

PubMed: 31283109
DOI: 10.1002/cmdc.201900287

実験手法

X-RAY DIFFRACTION (1.851 Å)