内吗啡肽2类似物的CoMFA研究
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摘要
内吗啡肽1(Tyr-Pro-Trp-Phe-NH_2,EM-1)和内吗啡2(Tyr-Pro-Phe-Phe,EM-2)是近年来发现的人体内生的,高选择性,高激动的μ-阿片受体的激动剂。它们具有最小阿片肽结构单元,并且具有强效的镇痛作用,但又有酶解稳定性不好,不易穿过血脑屏障的缺点,因此人们多以EMs为模板来设计新的类似物。但其结构柔性以及并未明确的构效关系,也大大阻碍了以其结构为模板的痛觉调节药物的研发。
本论文为了寻找新的具有更高μ阿片受体结合活性的EM-2的类似物,利用比较分子场分析方法(comparative molecular field analysis,CoMFA)方法,选择21个EM-2的类似物,进行了三维定量构效关系(3D-QSAR)研究。为了获得有统计意义的CoMFA模型,收集了许多不同实验的活性和结构数据,来进行CoMFA研究。最终所建立的CoMFA模型具有较好的预测性(q~2=0.634,R~2=0.970)。又选择了六个已知活性的类似物对于所建立的模型进行了验证,预测活性与实验测定的活性具有一致性。在该模型的基础上,设计了多个类似物,并预测了相应的活性值。本文为设计和寻找新的高结合活性EM-2类似物提供了有指导价值的信息。
Endomorphin-1(Tyr-Pro-Trp-Phe-NH_2 EM-1)and endomorphin-2(Tyr-Pro-Phe-Phe -NH_2,EM-2)are highly potent and selective endogenous ligands toμ-opioid receptor. Although they are the most small model peptides to reveal the function of opioid ligands, EMs were found to be easily digested by enzymes and hard to pass the blood-brain-barrier. To develop potent analogies with less side effects,many group have reported different methods to develop the more ideal analogs of EMs.However,their structure-activity relationship remains unclear,and no significant preference for subtype opioid receptor has been achieved.
In order to find new EM-2 analogs with superior property that target theμ-receptor, three-dimensional quantitative structure and activity relationship(3D-QSAR)studies were performed on 21 EM-2 analogs using comparative molecular field analysis(CoMFA).To obtain statistically significant and robust CoMFA models,21 EM-2 analogues were assembled by pooling biological and structural data from independent studies.The best predictive model for theμ-receptor were obtained with q2=0.634,r2=0.970.The models were further validated by a test set containing six compounds.Based on the model,several candidate structures were designed and predicted for thwir binding potencies.This study provides helpful information for designing new categoryμ-agonists from EMs.
本论文为了寻找新的具有更高μ阿片受体结合活性的EM-2的类似物,利用比较分子场分析方法(comparative molecular field analysis,CoMFA)方法,选择21个EM-2的类似物,进行了三维定量构效关系(3D-QSAR)研究。为了获得有统计意义的CoMFA模型,收集了许多不同实验的活性和结构数据,来进行CoMFA研究。最终所建立的CoMFA模型具有较好的预测性(q~2=0.634,R~2=0.970)。又选择了六个已知活性的类似物对于所建立的模型进行了验证,预测活性与实验测定的活性具有一致性。在该模型的基础上,设计了多个类似物,并预测了相应的活性值。本文为设计和寻找新的高结合活性EM-2类似物提供了有指导价值的信息。
Endomorphin-1(Tyr-Pro-Trp-Phe-NH_2 EM-1)and endomorphin-2(Tyr-Pro-Phe-Phe -NH_2,EM-2)are highly potent and selective endogenous ligands toμ-opioid receptor. Although they are the most small model peptides to reveal the function of opioid ligands, EMs were found to be easily digested by enzymes and hard to pass the blood-brain-barrier. To develop potent analogies with less side effects,many group have reported different methods to develop the more ideal analogs of EMs.However,their structure-activity relationship remains unclear,and no significant preference for subtype opioid receptor has been achieved.
In order to find new EM-2 analogs with superior property that target theμ-receptor, three-dimensional quantitative structure and activity relationship(3D-QSAR)studies were performed on 21 EM-2 analogs using comparative molecular field analysis(CoMFA).To obtain statistically significant and robust CoMFA models,21 EM-2 analogues were assembled by pooling biological and structural data from independent studies.The best predictive model for theμ-receptor were obtained with q2=0.634,r2=0.970.The models were further validated by a test set containing six compounds.Based on the model,several candidate structures were designed and predicted for thwir binding potencies.This study provides helpful information for designing new categoryμ-agonists from EMs.
引文
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[2]Hubbard R E.Can Drug Be Designed?.Curr Opin biotech,1997,8:696
[3]Wade R C.Flu' And Structure-based Drug Design.Structure,1997,5:1139
[4]Kuntz I D.Structure-based Strategies for Drug Design and Discovery.Science,1992,257:1078
[5]Veerapandian P.Structure-based Drug Design.New York:Marcel Dekker Inc,1997
[6]Leff P.Receptor-based Drug Design.New York:Marcel Dekker Inc,1998
[7]陈凯先 蒋华良 嵇汝运 计算机辅助药物设计 2000年10月 上海科学技术出版社
[8]Ang K K,McRitchie R J,Minson J B,et al.Activation of Spinal Opioid Receptor Contributes to Hypotension after Hemorrhage in Conscious Rates.Am J Physiol,1999,276(5Pt2):H1552
[9]Zadina JE,Hackler L,Ge L-J et al.A potent and selective endogenous agonist for the mu-opiate receptor.Nature,1997,386(6624):499-502.
[10]Martin-Schild S,Gerall AA,Kastin AJ et al.Differential distribution of endomorphin 1 and endomorphin 2 like immunoreactivities inthe CNSof the rodent.J Comp Neurol,1999,405(4):4502471.
[11]任维华 内吗啡肽研究进展 中国药理学通报 Chinese Pharmacological B ulletin 2001 Feb;17(1):17-20
[12]Hackler L,Zadina JE,Ge LJ.et al.Isolation of relatively large amounts of endomorphin-1 and endomorphin-2 from human brain cortex.Peptides,1997,18(10):1635-9
[13]Goldberg IE,Rossi GC,Letchworth SR et al.Pharmacological characterization of endomorphin-1 and endomorphin-2 in mouse brain.J Pharmacol Exp Ther,1998,286(2):1007-13.
[14] Harrison C, McNulty S, Smart D et al. The effects of endomorphin-1 and endomorphin-2 in CHO cells expressing recombinant mu-opioid receptors and SH-SY5Y cells. Br J Pharmacol, 1999, 128(2): 472-8
[15] Bryant SD, Attila M, Salvadori S et al. Molecular dynamics conformations of deltorphin analogues advocate delta opioid binding site models. Peptide Res. 1994, 7:175-184.
[16] Ouyang H, Vander Velde DG, Borchardt RT et al. Synthesis and conformational analysis of a coumarinic acid-based cyclic prodrug of an opioid peptide with modified sensitivity to esterase-catalyzed bioconversion. J Pept Res. 2002, 59(4): 183-95.
[17] Amodeo P, Guerrini R, Picone D et al. Solution structure of nociceptin peptides. J Pept Sci. 2002, 8(9): 497-509.
[18] Doi,M.,et al., Conserved and novel structure characteristics of enantiomorphic Leu-enkephalin. X-ray crystal analysis of Leu-enkephalin enantiomer, L-Tyr-Gly-Gly-D-Phe-D-Leu. Int J Pept Protein Res,1994,43(4):p. 325-31
[19] Ishida,T.,et al., X-ray diffraction studier of enkephalins. Crystal structure of [(4'-bromo)Phe4,Leu5]enkepphalin. Biochemiacl Journal, 1984.218(3):p.677-89
[20] Smith,D.and J.F. Griffin, Conformation of [Leu5]enkephalin from X-ray diffraction: features important for recognition at opiate receptor . Science, 1978. 199(4334): p.1214-1216
[21] Fournie Zaluski,M.C.,et al., Enkephalin related fragments. Conformational studies of the terapeptides Tyr-Gly-Gly-Phe and Gly-Gly-Phe-X(X=Leu, Met) by X-ray and 1H NMR spectroscopy. Biochemical and Biophysical Research Communications, 1977.79(4) p. 1199-1206.
[22] Gentilucci, L. and A. Tolomlli, Recent Advances in the Investigation of the Bioactive Conformation of Peptides Active at the mu-opioid Receptor. Conformational Analysis of Endomorphins. Current Topics in Medicinal Chemistry ,2004.4.p. 105-121.
[23] Podlogar BL, Paterlini MG, Ferguson DM et al. Conformational analysis of the endogenous m-opioid agonist endomorphin-1 using NMR spectroscopy and molecular modeling. FEBS Lett. 1998, 439, 13-20.
[24] Fiori S, Renner C, Cramer, Moroder L. Preferred Conformation of Endomorphin-1 in Aqueous and Membrane-Mimetic Environments. J. Mol. Biol. 1999,291,163-175.
[25] Yamazaki T, Ro S, Goodman M et al. A topochemical approach to explain morphiceptin bioactivity. J. Med. Chem. 1993, 36,708-719.
[26] Flippen-Anderson J, Deschamps JR, George C et al. X-ray structure of Tyr-D-Tic-Phe-Phe-NH2 (D-TIPP-NH2), a highly potent m-receptor selective opioid agonist. Comparisons with proposed model structures. J. Pept. Res. 1997,49, 384-393.
[27] Honda T, Shigehiro D, Okada K et al. Differential receptor binding characteristics of the phenylalanine residues at positions 3-4 of endomorphin-2. Pept. Sci. 2000, 37,139-142.
[28] In Y, Minoura K, Ohishi H et al. Conformational comparison of m-selective endomorphin-2 with its C-terminal free acid in DMSO solution, by 1H NMR spectroscopy and molecular modeling calculation. J. Pept. Res. 2001, 58, 399-412.
[29] In Y, et al. Structure function of C-terminal amidation of endomorphin . Conformational comparison of mu-selective endomorphin-2 with its C-terminal free acid,studied by 1H-NMR spectroscopy, molecular calculation, and X-ray crystallography. FEBS J. 2005.272.(19):p.5079-5097.
[30] Bala' zs Leitgeb et al. Conformational Analysis ofnEndomorphin-2 by Molecular Dynamics Methods. Biopolymers, Vol. 68, 497-511 (2003)
[31] Yusuke Sasaki et al. Endomorphin 2 Analogues Containing Dmp Residue as an Aromatic Amino Acid Surrogate with High mu-Opioid Receptor Affinity and Selectivity. Bioorganic & Medicinal Chemistry 11 (2003) 675-678
[32] Anna Janecka et al. Enzymatic degradation studies of endomorphin-2 and its analogs containing N-methylated amino acids Peptides. 2006 Jan;27(1): 131 -5
[33] Sasaki Y, Ambo A, Murase H et al. Synthesis and biological activity of opioid peptides replaced phenylalanine at position 3 or 4 by 2,6-dimethylphenylalanine. Pept. Sci. 2000,37,117-120.
[34] Harrison BA, Pasternak GW, Verdine G et al. L-2,6-Dimethyltyrosine Analogues of a Stereodiversified Ligand Library:Highly Potent, Selective, Non-Peptidic m Opioid Receptor Agonists. J. Med. Chem. 2003; 46, 677-680.
[35] Fujita Y, Shimizu Y, Takahashi M et al. Synthesis of endomorphin-2 analogues, studies on their activities for opioid receptors, and three dimensional structure. Pept. Sci. 2001,38,105-108.
[36]Sasaki Y,Sasaki A,Niizuma H et al.Endomorphin 2 analogues containing Dmp residue as an aromatic amino acid surrogate with high m-opioid receptor affinity and selectivity.Bioor.Med.Chem.2003,11,675-678.
[37]Lengyel I,Orosz G,Biyashev D et al.Side Chain Modifications Change the Binding and Agonist Properties of Endomorphin 2.Biochem.Biophys.Res.Commun.2002,290,153-161.
[38]In Y,Minoura K,Ishida T et al.Functional analysis of C-terminal amide in bioactivity of endomorphin-2:conformational comparison with its unamidated peptide in DMSO solution.Pept.Sci.2000,37,313-316.
[39]Shimizu Y,Takahashi M,Fukumizu A et al.Synthesis of endomorphin analogs and studies on the structure-opioid receptor-binding activity relationship.Pept.Sci.1999,35,197-200.
[40]Rapada R S,Porreca F.Development of delta Opioid Receptors as Nonaddicting Analgesica.Pharma Res,1991,8:1
[41]Ma L,Cheng Z J,Pei G,et al.Function Expression,Activation and Desensitization of Opioid Receptor-like Receptor ORL1 in Neuroblastoma~Glioma NG108-15 Hybrid Cells.FEBS Lett,1997,403:91
[42]刘威,段海清等,阿片受体的研究进展 生物技术通讯 vol.14 NO.3 May,2003
[43]Palczewski,K.et al.(2000)Crystal structure of rhodopsin:a G proteincoupled,receptor.Science 289,739-745
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