5VUC

Pim1 Kinase in complex with a benzofuranone inhibitor

5VUC の概要

• エントリーDOI: 10.2210/pdb5vuc/pdb
• 分子名称: Serine/threonine-protein kinase pim-1, GLYCEROL, (2Z)-2-(1H-indol-3-ylmethylidene)-6-methoxy-7-(piperazin-1-ylmethyl)-1-benzofuran-3-one, ... (4 entities in total)
• 機能のキーワード: pim1 kinase, kinase inhibitor, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34685.27

構造登録者

Parker, L.J. (登録日: 2017-05-18, 公開日: 2017-12-13, 最終更新日: 2024-11-06)

主引用文献

Watanabe, C.,Watanabe, H.,Fukuzawa, K.,Parker, L.J.,Okiyama, Y.,Yuki, H.,Yokoyama, S.,Nakano, H.,Tanaka, S.,Honma, T.
Theoretical Analysis of Activity Cliffs among Benzofuranone-Class Pim1 Inhibitors Using the Fragment Molecular Orbital Method with Molecular Mechanics Poisson-Boltzmann Surface Area (FMO+MM-PBSA) Approach
J Chem Inf Model, 57:2996-3010, 2017

PubMed Abstract: Significant activity changes due to small structural changes (i.e., activity cliffs) of serine/threonine kinase Pim1 inhibitors were studied theoretically using the fragment molecular orbital method with molecular mechanics Poisson-Boltzmann surface area (FMO+MM-PBSA) approach. This methodology enables quantum-chemical calculations for large biomolecules with solvation. In the course of drug discovery targeting Pim1, six benzofuranone-class inhibitors were found to differ only in the position of the indole-ring nitrogen atom. By comparing the various qualities of complex structures based on X-ray, classical molecular mechanics (MM)-optimized, and quantum/molecular mechanics (QM/MM)-optimized structures, we found that the QM/MM-optimized structures provided the best correlation (R = 0.85) between pIC and the calculated FMO+MM-PBSA binding energy. Combining the classical solvation energy with the QM binding energy was important to increase the correlation. In addition, decomposition of the interaction energy into various physicochemical components by pair interaction energy decomposition analysis suggested that CH-π and electrostatic interactions mainly caused the activity differences.

PubMed: 29111719
DOI: 10.1021/acs.jcim.7b00110

実験手法

X-RAY DIFFRACTION (2 Å)