8AFR

Pim1 in complex with 4-((6-hydroxybenzofuran-3-yl)methyl)benzoic acid and Pimtide

8AFR の概要

• エントリーDOI: 10.2210/pdb8afr/pdb
• 関連するPDBエントリー: 7QB2 7QFM 7Z6U
• 分子名称: Serine/threonine-protein kinase pim-1, Pimtide, 4-((6-hydroxybenzofuran-3-yl)methyl)benzoic acid, ... (4 entities in total)
• 機能のキーワード: serine kinase, kinase, complex, pim1, pim, pim-1, inhibitor, tumorigenisis, cancer, pimtide, proto oncogen, atp, phosphorylation, apoptosis, cell cycle, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 37217.26

構造登録者

Hochban, P.M.M.,Heine, A.,Diederich, W.E. (登録日: 2022-07-18, 公開日: 2023-02-01, 最終更新日: 2024-11-13)

主引用文献

Heyder, L.,Hochban, P.M.M.,Taylor, C.,Chevillard, F.,Siefker, C.,Iking, C.,Borchardt, H.,Aigner, A.,Klebe, G.,Heine, A.,Kolb, P.,Diederich, W.E.
Pose, duplicate, then elaborate: Steps towards increased affinity for inhibitors targeting the specificity surface of the Pim-1 kinase.
Eur.J.Med.Chem., 245:114914-114914, 2023

PubMed Abstract: In this study, fragment-sized hits binding to Pim-1 kinase with initially modest affinity were further optimized by combining computational, synthetic and crystallographic expertise, eventually resulting in potent ligands with affinities in the nanomolar range that address rarely-targeted regions of Pim-1 kinase. Starting from a set of crystallographically validated, chemically distinct fragments that bind to Pim-1 kinase but lack typical nucleotide mimetic structures, a library of extended fragments was built by exhaustive in silico reactions. After docking, minimization, clustering, visual inspection of the top-ranked compounds, and evaluation of ease of synthetic accessibility, either the original compound or a close derivative was synthesized and tested against Pim-1. For compounds showing the highest degree of Pim-1 inhibition the binding mode was determined crystallographically. Following a structure-guided approach, these were further optimized in a subsequent design cycle improving the compound's initial affinity by several orders of magnitude while synthesizing only a comparatively modest number of derivatives. The combination of computational and experimental approaches resulted in the development of a reasonably potent, novel molecular scaffold for inhibition of Pim-1 that targets specific surface regions, such as the interaction with R122 and P123 of the hinge region, which has been less frequently investigated in similar studies.

PubMed: 36410167
DOI: 10.1016/j.ejmech.2022.114914

実験手法

X-RAY DIFFRACTION (2.15 Å)