7N2A
human PXR LBD bound to compound 2
Summary for 7N2A
| Entry DOI | 10.2210/pdb7n2a/pdb |
| Descriptor | 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) |
| Functional Keywords | nuclear receptor, helical sandwich, xenobiotics, gene regulation |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 34602.03 |
| Authors | Williams, S.P.,Wisely, G.B.,Ramanjulu, J.M. (deposition date: 2021-05-28, release date: 2021-08-25, Last modification date: 2023-10-18) |
| Primary citation | 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 Cited by 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: 34531948DOI: 10.1021/acsmedchemlett.1c00187 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.26 Å) |
Structure validation
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