5VUA
Pim1 Kinase in complex with a benzofuranone inhibitor
Summary for 5VUA
| Entry DOI | 10.2210/pdb5vua/pdb |
| Descriptor | Serine/threonine-protein kinase pim-1, GLYCEROL, PHOSPHATE ION, ... (5 entities in total) |
| Functional Keywords | pim1 kinase, kinase inhibitor, transferase |
| Biological source | Homo sapiens (Human) |
| Cellular location | Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309 |
| Total number of polymer chains | 1 |
| Total formula weight | 34765.23 |
| Authors | Parker, L.J. (deposition date: 2017-05-18, release date: 2017-12-13, Last modification date: 2024-03-20) |
| Primary citation | 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 Cited by 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: 29111719DOI: 10.1021/acs.jcim.7b00110 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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