Journal
JOURNAL OF CHEMICAL INFORMATION AND MODELING
Volume 57, Issue 12, Pages 2996-3010Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.7b00110
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Funding
- Research and Development for Next-Generation Information Technology of the Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- JSPS KAKENHI from MEXT [JP15K05397, JP15K21632, 26460035]
- Japan Agency for Medical Research and Development (AMED)
- Grants-in-Aid for Scientific Research [17H06353, 15K05397] Funding Source: KAKEN
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Significant activity changes due to small structural changes (i.e., activity cliffs) of serine/threonine kinase Pimi 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 Pimi, 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-2= 0.85) between pIC(50)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-pi and electrostatic interactions mainly caused the activity differences.
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