7JXT

Ovine COX-1 in complex with the subtype-selective derivative 2a

7JXT の概要

• エントリーDOI: 10.2210/pdb7jxt/pdb
• 分子名称: Prostaglandin G/H synthase 1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, PROTOPORPHYRIN IX CONTAINING FE, ... (4 entities in total)
• 機能のキーワード: cyclooxygenase-1, oxidoreductase inhibitor, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• 由来する生物種: Ovis aries (Sheep)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 132390.55

構造登録者

Ko, Y.,Iaselli, M.,Miciaccia, M.,Friedrich, L.,Schneider, G.,Scilimati, A.,Cingolani, G. (登録日: 2020-08-27, 公開日: 2021-09-01, 最終更新日: 2024-10-30)

主引用文献

Friedrich, L.,Cingolani, G.,Ko, Y.H.,Iaselli, M.,Miciaccia, M.,Perrone, M.G.,Neukirch, K.,Bobinger, V.,Merk, D.,Hofstetter, R.K.,Werz, O.,Koeberle, A.,Scilimati, A.,Schneider, G.
Learning from Nature: From a Marine Natural Product to Synthetic Cyclooxygenase-1 Inhibitors by Automated De Novo Design.
Adv Sci, 8:e2100832-e2100832, 2021

PubMed Abstract: The repertoire of natural products offers tremendous opportunities for chemical biology and drug discovery. Natural product-inspired synthetic molecules represent an ecologically and economically sustainable alternative to the direct utilization of natural products. De novo design with machine intelligence bridges the gap between the worlds of bioactive natural products and synthetic molecules. On employing the compound Marinopyrrole A from marine Streptomyces as a design template, the algorithm constructs innovative small molecules that can be synthesized in three steps, following the computationally suggested synthesis route. Computational activity prediction reveals cyclooxygenase (COX) as a putative target of both Marinopyrrole A and the de novo designs. The molecular designs are experimentally confirmed as selective COX-1 inhibitors with nanomolar potency. X-ray structure analysis reveals the binding of the most selective compound to COX-1. This molecular design approach provides a blueprint for natural product-inspired hit and lead identification for drug discovery with machine intelligence.

PubMed: 34176236
DOI: 10.1002/advs.202100832

実験手法

X-RAY DIFFRACTION (3.35 Å)