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QM/MM based 3D QSAR models for potent B-Raf inhibitors

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Abstract

Three dimensional (3D) quantitative structure-activity relationship studies of 37 B-Raf inhibitors, pyrazole-based derivatives, were performed. Based on the co-crystallized compound (PDB ID: 3D4Q), several alignment methods were utilized to derive reliable comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. Receptor-guided alignment with quantum mechanics/molecular mechanics (QM/MM) minimization led to the best CoMFA model (q 2 = 0.624, r 2 = 0.959). With the same alignment, a statistically reliable CoMSIA model with steric, H-bond acceptor, and hydrophobic fields was also derived (q 2 = 0.590, r 2 = 0.922). Both models were validated with an external test set, which gave satisfactory predictive r 2 values of 0.926 and 0.878, respectively. Contour maps from CoMFA and CoMSIA models revealed important structural features responsible for increasing biological activity within the active site and explained the correlation between biological activity and receptor-ligand interactions. New fragments were identified as building blocks which can replace R1-3 groups through combinatorial screening methods. By combining these fragments a compound with a high bioactivity level prediction was found. These results can offer useful information for the design of new B-Raf inhibitors.

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Acknowledgments

We thank Jung Soo Oh of Computational Science Center, Future Fusion Technology Division, at KIST for helpful discussions. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009-0072095; AEC, JYC) and (2009-0087992; JMH).

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Authors and Affiliations

  1. Department of Biotechnology and Bioinformatics, Korea University, Jochiwon-Eup, Yeongi-Gun, Chungnam, 339-700, Korea

    Jae Yoon Chung & Art E. Cho

  2. Life Sciences Research Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul, 130-650, South Korea

    Jae Yoon Chung & Jung-Mi Hah

  3. Computational Science Center, Future Fusion Technology Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul, 130-650, South Korea

    Hwan Won Chung

  4. Research Center for Resistant Cells, Chosun University, Gwangju, 501-759, Korea

    Seung Joo Cho

  5. Department of Cellular and Molecular Medicine, College of Medicine, Chosun University, 375 Seosuk-Dong, Dong-Gu, Gwangju, 501-759, Korea

    Seung Joo Cho

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  1. Jae Yoon Chung
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  2. Hwan Won Chung
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  5. Art E. Cho
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Correspondence to Art E. Cho.

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Chung, J.Y., Chung, H.W., Cho, S.J. et al. QM/MM based 3D QSAR models for potent B-Raf inhibitors. J Comput Aided Mol Des 24, 385–397 (2010). https://doi.org/10.1007/s10822-010-9337-5

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  • DOI: https://doi.org/10.1007/s10822-010-9337-5

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