7N2A

human PXR LBD bound to compound 2

7N2A の概要

• エントリーDOI: 10.2210/pdb7n2a/pdb
• 分子名称: Isoform 1C of Nuclear receptor subfamily 1 group I member 2, 5-benzyl-2-(3-fluoro-2-hydroxyphenyl)-6-methyl-3-(2-phenylethyl)pyrimidin-4(3H)-one (3 entities in total)
• 機能のキーワード: nuclear receptor, helical sandwich, xenobiotics, gene regulation
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34602.03

構造登録者

Williams, S.P.,Wisely, G.B.,Ramanjulu, J.M. (登録日: 2021-05-28, 公開日: 2021-08-25, 最終更新日: 2023-10-18)

主引用文献

Ramanjulu, J.M.,Williams, S.P.,Lakdawala, A.S.,DeMartino, M.P.,Lan, Y.,Marquis, R.W.
Overcoming the Pregnane X Receptor Liability: Rational Design to Eliminate PXR-Mediated CYP Induction.
Acs Med.Chem.Lett., 12:1396-1404, 2021

PubMed Abstract: The pregnane X receptor (PXR) regulates expression of proteins responsible for all three phases required for the detoxification mechanism, which include CYP450 enzymes, phase II enzymes, and multidrug efflux pumps. Therefore, PXR is a prominent receptor that is responsible for xenobiotic excretion and drug-drug interactions. Pyrimidinone is an antagonist of the calcium sensing receptor (CaSR) and a strong activator of PXR. Repeat oral administration revealed diminished exposures over time, which prohibited further progression. A medicinal chemistry campaign was initiated to understand and abolish activation of PXR in order to increase systemic exposures. Rational structure-activity relationship investigations utilizing cocrystal structures and a de novo pharmacophore model resulted in compounds devoid of PXR activation. These studies culminated in the first orally active CaSR antagonist suitable for progression. Cocrystallography, the pharmacophore model employed, and additional observations reported herein supported rational elimination of PXR activation and have applicability across diverse chemical classes to help erase PXR-driven drug-drug interactions.

PubMed: 34531948
DOI: 10.1021/acsmedchemlett.1c00187

実験手法

X-RAY DIFFRACTION (2.26 Å)