Bulletin of the Korean Chemical Society

  • 제27권10호
  • /
  • Pages.1531-1536
  • /
  • 2006
  • /
  • 0253-2964(pISSN)
  • /
  • 1229-5949(eISSN)
대한화학회 (Korean Chemical Society)
권호 표지
DOI QR코드

DOI QR Code

HQSAR Study of Microsomal Prostaglandin E2 Synthase (mPGES-1) Inhibitors

  • San Juan, Amor A. (Biochemicals Research Center, Korea Institute of Science and Technology) ;
  • Cho, Seung-Joo (Biochemicals Research Center, Korea Institute of Science and Technology) ;
  • Cho, Hoon (College of Engineering, Chosun University)
  • 발행 : 2006.10.20
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Microsomal prostaglandin $E_2$ synthase (mPGES-1) is an enzyme that is associated with inflammation, pain, fever and cancer. Hologram quantitative structure activity relationship (HQSAR) was conducted on the series of MK-886 compounds acting as mPGES-1 inhibitors. A training set with 24 compounds was used to establish the HQSAR model. The best model was chosen based on the cross-validated correlation coefficient ($q^2$=0.884) and the correlation coefficient($r^2$=0.976). The model was utilized to predict the activity of the eight-test set of compounds giving the predictive $r^2$ value of 0.845. The descriptors of the model are based on fragment distinction (atoms, bond and connectivity) and fragment size (2-5 atoms). The atomic contribution maps generated from HQSAR were useful in identifying the important structural features responsible for the inhibitory activity of MK-886 inhibitors. Based on the generated model, the presence of hydrophobic biphenyl group seems to enhance inhibition of mPGES-1 that is in agreement with the previous experiments. In addition, it seems important for a halogen to be substituted to the biphenyl ring and for an acyl group to be attached to the indole moiety for enhanced activity.

키워드

참고문헌

  1. Kudo, I.; Murakami, M.; Prostaglandin, E. J. Biochem. Mol. Biol. 2005, 38(6), 633-638 https://doi.org/10.5483/BMBRep.2005.38.6.633
  2. Shinji, Y.; Tsukui, T.; Tatsuguchi, A.; Shinoki, K.; Kusunoki, M.; Suzuki, K.; Hiratsuka, T.; Wada, K.; Futagami, S.; Miyake, K.; Gudis, K.; Sakamoto, C. Am. J. Physiol. Gastrointest Liver Physiol. 2005, 288, G308-G315 https://doi.org/10.1152/ajpgi.00313.2004
  3. Ek, M.; Engblom, D.; Saha, S.; Blomqvist, A.; Jakobsson, P.; Ericsson-Dahlstrand, A. Nature 2001, 410, 430-443
  4. Thoren, S.; Jakobsson, P. J. Eur. J. Biochem. 2000, 267, 6428- 6434 https://doi.org/10.1046/j.1432-1327.2000.01735.x
  5. Lowis, D. R. Tripos Technical Notes 1997, 1, 1-16
  6. Riendeau, D.; Aspiotis, R.; Ethier, D.; Gareau, Y.; Grimm, E.; Guay, J.; Guiral, S.; Juteau, H.; Mancini, J.; Methot, N.; Rubin, J.; Friesen, R. Bioorg. Med. Chem. Lett. 2005, 15, 3352- 3355 https://doi.org/10.1016/j.bmcl.2005.05.027
  7. Flower, D. J. Chem. Inf. Comput. Sci. 1997, 38(3), 379- 386
  8. Cho, S. J. Bull. Korean Chem. Soc. 2005, 26(1), 85-90 https://doi.org/10.5012/bkcs.2005.26.1.085
  9. SYBYL 7.0; Tripos Inc.: St. Louis, 2004
  10. Cramer, R. D. III; Bunce, J. D.; Patterson, D. E. Quant. Struct. Act. Relat. 1998, 7, 18-25
  11. Wold, S.; Albano, C.; Dunn, W.; Edlund, U.; Esbensen, K.; Geladi, P.; Hellberg, S.; Johansson, E.; Lindberg, W.; Sjosstrom, M. In Chemometrics: Mathematics and Statistics in Chemistry; Kowalski, B., Ed.; Reidel, Dordrecht, The Netherlands, 1987; pp 17-95
  12. Bush, B. L.; Nachbar, R. B. J. Comput. Aided Mol. Des. 1993, 7, 587-619 https://doi.org/10.1007/BF00124364
  13. Quraishi, O.; Mancini, J.; Rindeau, D. Biochem. Pharma. 2002, 63, 1183-1189 https://doi.org/10.1016/S0006-2952(02)00844-4

피인용 문헌

  1. Physical Chemistry Research Articles Published in the Bulletin of the Korean Chemical Society: 2003-2007 vol.29, pp.2, 2008, https://doi.org/10.5012/bkcs.2008.29.2.450
  2. Docking and Quantum Mechanics-Guided CoMFA Analysis of b-RAF Inhibitors vol.29, pp.8, 2006, https://doi.org/10.5012/bkcs.2008.29.8.1499
  3. Structure-Based Discovery of Inhibitors of Microsomal Prostaglandin E2 Synthase−1, 5-Lipoxygenase and 5-Lipoxygenase-Activating Protein: Promising Hits for the Development of New Anti vol.54, pp.6, 2011, https://doi.org/10.1021/jm101238d