TY - JOUR
T1 - 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
AU - Watanabe, Chiduru
AU - Watanabe, Hirofumi
AU - Fukuzawa, Kaori
AU - Parker, Lorien J.
AU - Okiyama, Yoshio
AU - Yuki, Hitomi
AU - Yokoyama, Shigeyuki
AU - Nakano, Hirofumi
AU - Tanaka, Shigenori
AU - Honma, Teruki
N1 - Funding Information:
The authors thank Prof. Yuji Mochizuki and Dr. Toru Sengoku for technical support and help with preparation of the manuscript and Dr. Noriaki Hashimoto, Dr. Daisuke Takaya, and Dr. Tomohiro Sato for fruitful discussions. This research was a part of the “Research and Development of Innovative Simulation Software” Project supported by the Research and Development for Next-Generation Information Technology of the Ministry of Education, Culture, Sports, Science and Technology (MEXT). This work was supported by JSPS KAKENHI Grants JP15K05397, JP15K21632, and 26460035, the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from MEXT, and the Japan Agency for Medical Research and Development (AMED). This research in part made use of the computational resources of the RICC (RIKEN Integrated Cluster of Clusters) and the π-VizStudio at Kobe University.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/12/26
Y1 - 2017/12/26
N2 - 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 (R2 = 0.85) between pIC50 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.
AB - 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 (R2 = 0.85) between pIC50 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.
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U2 - 10.1021/acs.jcim.7b00110
DO - 10.1021/acs.jcim.7b00110
M3 - Article
C2 - 29111719
AN - SCOPUS:85039999905
VL - 57
SP - 2996
EP - 3010
JO - Journal of Chemical Documentation
JF - Journal of Chemical Documentation
SN - 0095-2338
IS - 12
ER -