Actas de congresos
Molecular Modeling Of The Inhibition Of Enzyme Pla2 From Snake Venom By Dipyrone And 1-phenyl-3-methyl-5-pyrazolone
Registro en:
International Journal Of Quantum Chemistry. , v. 108, n. 13, p. 2576 - 2585, 2008.
207608
10.1002/qua.21656
2-s2.0-52449108369
Autor
Da Silva S.L.
Comar Jr. M.
Oliveira K.M.T.
Chaar J.S.
Bezerra E.R.M.
Calgarotto A.K.
Baldasso P.A.
Veber C.L.
Villar J.A.F.P.
Oliveira A.R.M.
Marangoni S.
Institución
Resumen
Phospholipases A2 (PLA2) are enzymes that trigger the degradation cascade of the arachidonic acid, leading to the formation of pro-inflammatory eicosanoids. The selective inhibition of PLA2S is crucial in the search for a more efficient anti-inflammatory drug with fewer side effects than the drugs currently used. Hence, we studied the influences caused by two pyrazolonic inhibitors: dipyrone (DIP) and 1-phenyl-3-methyl-5- pyrazolone (PMP) on the kinetic behavior of PLA2 from Crotalus adamanteus venom. Molecular modeling results, by DFT and MM approaches, showed that DIP is strongly associated to the active site of PLA2 through three hydrogen bonds, whereas PMP is associated to the enzyme just through hydrophobic interactions. In addition, only PMP presents an intramolecular hydrogen bond that make difficult the formation of more efficient interactions with PLA2. These results help in the understanding of the experimental observations. Experimentally, the results showed that PLA 2 from C. adamanteus present a typical Michaelian behavior. In addition, the calculated kinetic parameters showed that, in the presence of DIP or PMP, the maximum enzymatic velocity (VMAX) value was kept constant, whereas the Michaelis constant (KM) values increased and the inhibition constant (XI) decreased, indicating competitive inhibition. These results show that the phenyl-pyrazolonic structures might help in the development and design of new drugs able to selectively inhibit PLA 2. © 2008 Wiley Periodicals, Inc. 108 13 2576 2585 Ikai, K. J. Dermatol Sci 1999, 21, 135Funk, C.D., (2001) Science, 294, p. 1871 Yeddar, S., Lichtenberg, D., Schnitzer, E., (2000) Biochim Biophys Acta, 1488, p. 182 Diaz, B.L., Arm, J.P., (2003) Prostaglan Leuk Ess Fatty Acids, 69, p. 87 Balsinde, J., Winstead, M.V., Dennis, E.A.F.L., (2002), 531 (2)Murakami, M., Shimbara, S., Kambe, T., Kuwata, H., Winstead, M.V., Tischfield, J.A., Kubo, I., (1998) J Biol Chem, 273, p. 14411 Snyder, F., (1995) Biochem J, 305, p. 689 Huwiler, A., Staudt, G., Kramer, R.M., Pfeilschifter, J., (1997) Biochim Biophys Acta, 1348, p. 257 Wijkander, J., O'Flaherty, J.T., Nixon, A.B., Wykle, R.L., (1995) J Biol Chem, 270, p. 26543 Yedgar, S., Cohen, Y., Shoseyov, D., (2006) Biochim Biophys Acta, 1761, p. 1373 Teixeira, C.F.P., Landucci, E.C.T., Antunes, E., Chacur, M., Cury, Y., (2003) Toxicon, 42, p. 947 Singh, N., Jabeen, T., Somvanshi, R.K., Sharma, S., Dey, S., Singh, T.P., (2004) Biochemistry, 43, p. 14577 Singh, R.K., Ethayathulia, A.S., Jabeen, T., Sharma, S., Kaur, P., Singh, T.P., (2005) J Drug Target, 13, p. 113 Jabeen, T. Singh, N. Singh, R. K. Sharma, S. Somvanshi, R. K. Dey, S. Singh, T. P. Acta Crystallografica 2005, 61, 1579Masoud, M.S., Abd El Zaber Mostafa, M., Ahmed, R.H., Abd El Moneim, N.H., (2003) Molecules, 8, p. 430 Wells, M.A., (1971) Biochemistry, 10, p. 4074 Wells, M.A., (1971) Biochemistry, 10, p. 4078 Smith, C.M., Wells, M.A., (1981) Biochim Biophys Acta, 663, p. 687 Tsao, F.H.C., Keim, P.S., Heinrikson, R.L., (1975) Arch Biochem Biophys, 167, p. 706 Samejima, Y., Aoki, Y., Mebs, D., (1991) Toxicon, 29, p. 461 Schägger, H., Von Jagow, G., (1987) Anal Biochem, 166, p. 368 Souza, A.D.L., Rodrigues-Filho, E., Souza, A.Q.L., Pereira, J.O., Calgarotto, A.K., Maso, V., Marangoni, S., Da Silva, S.L., (2008) Toxicon, 51, p. 240 Brunie, S., Bolin, J., Gewirth, D., Sigler, P.B., (1985) J Biol Chem, 260, p. 9742 Ami, R.K., Ward, R.J., (1996) Toxicon, 34, p. 827 Berg, O.G., Gelb, M.H., Tsai, M.-D., Jain, M.K., (2001) Chem Rev, 101, p. 2613 Jorgensen, W.L., Tirado-Rives, J., (1988) J Am Chem Soc, 110, p. 1657 Gaussian 03, Revision C. 02, Gaussian, Inc., Wallingford, CT, USA, 2004HyperChem, Release 7.51 for Windows, Molecular Modeling System, Gainesville, FL, USA, 2005GaussView for Windows, Release 3.09, Gaussian, Inc, Wallingford, CT, USA, 2004Shimomura, O., Lee, B.S., Meth, S., Suzuki, H., Mahajan, S., Nomura, R., Janda, K.D., (2005) Tetrahedron, 61, p. 12160 Makhija, M.T., Kasliwal, R.T., Kulkarni, V.M., Neamati, N., (2004) Bioorg Med Chem, 12, p. 2317 Beghini, D.G., Toyama, M.H., Hyslop, S., Sodek, L.C., Novello, J.C., Marangoni, S., (2000) J Prot Chem, 19, p. 679 Bentur, Y., Cohen, O., (2004) J Toxicol-Clin Toxicol, 42, p. 261 Xu, S., Gu, L., Jiang, T., Zhou, Y., Lin, Z., (2003) Biochem Biophys Res Comm, 300, p. 271 Tatsuo, M.A.K.F., Carvalho, W.M., Silva, C.V., Miranda, A.E.G., Ferreira, S.H., Francischi, J.N., (1994) Inflammation, 18, p. 399 Camu, F., Vanlersberghe, C., (2002) Best Pract Res Clin Anaesthesiol, 16, p. 475 Fendrich, Z., (2002) Casopis Lekaru Ceskych, 139, p. 440 Da Silva, S.L., Calgarotto, A.K., Maso, V., Damico, D.C.S., Baldasso, P.A., Veber, C.L., Villar, J.A.F.P., Marangoni, S., European Journal of Medicinal Chemistry, 2008. , doi: 10.1016/j.ejmech.2008.02.043