Äîêóìåíò âçÿò èç êýøà ïîèñêîâîé ìàøèíû. Àäðåñ îðèãèíàëüíîãî äîêóìåíòà : http://www.mce.biophys.msu.ru/archive/doc21925/doc.pdf Äàòà èçìåíåíèÿ: Wed Jul 30 15:01:58 2008 Äàòà èíäåêñèðîâàíèÿ: Mon Oct 1 21:47:56 2012 Êîäèðîâêà:

. ., . ., . ., . . , , . , ­ Boc-Glu-Orn-OBut Boc-Asp-Lys-OBut , ­ Boc-Glu- -Lys-OBut Boc-Asp- -Lys-OBut . . , . . , «». «» . . - [1]. [2-4], - [5], [68], [9] [10-15] - . , , , Lys Orn Glu Asp ­ [3, 10-14, 16-21]. , [14], , [21]. , , . , ,


. . [22-24] Ac­Lys­Asp­NHMe , H­Lys­Asp­OH H­Glu­Lys­OH , [21]. [21], ­ Boc-Glu-Orn-OBut Boc-Asp-Lys-OBut , ­ Boc-Glu- -Lys-OBut Boc-Asp- -Lys-OBut . . CHARMM [25], . E , , . , =10 =4. - 1000 . E 20 /, - - « » E 10 /. , 30°. , , 20°. 1000 « ». . , 40000 . E 3.5 /. =10 . . [25] , -


Asp, Lys, Glu Orn: Boc-Glu-Orn-OBut (I), Boc-Asp-Lys-OBut (II), Boc-Glu- -Lys-OBut (III) Boc-Asp- -Lys-OBut (IV) (.1). : I II , III IV .
O


2 1

3 1

CH2

C

4 2

N H H N

CH

3 2 2
CH2

O


C N H

5 2
CH
2

4 2
CH2


CH3 CH3 C CH3 CH
3

2 1

3 2 2 2
CH3 C CH3 CH3

CH3 CH
3

CH3 C

0 0
O

O C

0
N H

11

CH2 CH

2
CH C O

CH2

2 2

CH3

1



C
1

1

1 2 2

CH3

0 0 C0 C
O

O

1 1

CH2 CH H N C
1

CH2

2
CH C O

CH2

O

N H

1



1



1 2
2

2 O 3

O

2 O 3

Boc-Glu-Orn-OBut (I)
2 O 3
C CH3 C CH CH
3 3

Boc-Asp-Lys-OBut (II)
3
C CH3 CH3 CH3

O O
3 1

O O

2 O
C


CH3 CH CH3 C
3

2 1

CH2

C



2
N H



2

CH

1 2

CH2 CH2

0 0
O

O C

CH2

2 2
3


CH3 CH3 CH3


2 1

C

2
N H H



2

CH

1 2
CH2 CH2 CH2

CH2

2 2

0
N H

11 1

CH

1 N
C
1

H



5 CH 2

CH 2 2
2

4 2

C0

0
O

O C

0
N H

1 1

CH

1 N
C
1

3 2

1



4 5 CH2 2 2

O

O

Boc-Glu

Lys-OBut (III)

Boc-Asp

Lys-OBut (IV)

. 1. Boc-Glu-Orn-OBut (I), Boc-Asp-Lys-OBut (II), Boc-Glu- -Lys-OBut (III), Boc-Asp- -Lys-OBut (IV) .

, , E < 3.5 /. . - , -C(CH3)3, - 0 , 3 ±60° 180° ( ±10°). «» 0, 0 , 2 180 ± 10° (.1). I II (11), (.1). I ( 11 12), II - (11). II , (. 1). , ~6 / . , I -


E<3.5 / , E (. 1). (=10) 1, (=4) 3. - - .
1. ,
Boc-Glu-Orn-OBut

E, / =10 =4 1 0.0 0.2 2 2.3 0.8 3 2.5 0.0 4 2.9 3.4 5 3.5 2.0

(I) 13 21 Orn 22 23 24 -70 55 66 -172 51 60 -146 3 -52 -57 140 -1 -70 -57 150 0 71 59 -153 2

1 1 133 4 -25 177 145 -173 0 -176 98 172

Glu 11 -164 75 176 62 -174

12

2 -62 133 -88 -55 -55 125 -83 -76 55 -133 -42 74 80 -108 -163 58 -78 102 72 -59
t

Boc-Asp-Lys-OBu

E, / =10 =4 1 1 0.0 -1.2 -33

(II) (.) Asp Lys 1 11 12 2 21 22 23 24 25 -174 58 86 -140 75 -63 -65 74 90 -168

I_1

I_3

II

. 2. - . 3. Boc-Glu-Orn-OBut Boc-Asp-Lys-OBut (II) ­ ( I_1 (); I_3 () )

a



I_1 () . N- C- , - , () (. 2). I_3 , I_1, -


(. 2). N- C- . II - N- C- (. 3). (.1) . Boc-Glu- -Lys-OBut (III) Boc-Asp- -Lys-OBut (IV), , 12 11 - (. 1). III, IV, , . , IV (.2).
2. ,
Boc-Glu- -Lys-OBut

(III) Lys

E, / =10 =4 1 0.0 1.4 2 0.5 4.3 3 0.6 0.0 4 0.7 6.4 5 2.0 3.7 6 2.2 6.3 7 2.8 7.9 8 3.1 6.6 E, / =10 =4 1 0.0 -1.6

1 1 -166 169 156 172 -20 -169 122 171 101 173 103 172 -55 -174 108 161

Glu 11 52 59 70 -172 -170 -169 -167 179

12 61 69 -56 -67 -70 -69 -66 56
t

13 81 79 109 130 140 141 -90 -85

2 -90 -168 -110 -87 -168 -114 63 -37

21 -54 58 64 -55 58 -55 57 -64 (IV)

22 -70 -169 -62 -70 -169 -60 169 64

23 70 60 -63 71 59 168 -60 61

24 54 54 65 54 54 -58 -54 -68

25 -170 -127 133 -165 -125 -74 133 -105

-167 -167 -161 -165 -166 -168 165 171

Boc-Asp- -Lys-OBu

Asp 1 -30 1 -170 11 58 12 2 84 -140 21 76 Lys 22 -63 23 24 -66 73 25 88 -169

(=10) III_1 «» - , 90° (. 4). , III_3 (=4) - ~45° (. 4). N- C- .


IV (.5) - N- C- , .
III_1 III_3

IV_1

a



. 4. - .5 . Boc-Glu- -Lys-OBut ­ (- III_1 (); III_3 () ) Boc-Asp- -Lys-OBut (IV)

.1, Boc-Asp-Lys-OBut (II) Boc-Asp- -Lys-OBut (IV) , N- C- . IV II (.6, .1-2). , (11) Boc-Asp-Lys-OBut (II) Boc-Asp- -Lys-OBut (IV).
- (II)

- (IV)

N- (II, IV)
. 6. Boc-Asp-Lys-OBut (II) Boc-Asp- -Lys-OBut (IV).

(I-IV) . - ( NO >3.3å) -


N-H··C=O (C=OH 50­90°).

2

180 150 120 90 60 30 0 -30 -60 -90 -120 -150 -180 -180 -150 -120 -90 -60 -30 0



. 7 1 2, N-, C Boc-Glu-Orn-OBut ( ; I), Boc-Asp-Lys-OBut ( ; II), Boc-Glu- -Lys-OBut ( ; III) Boc-Asp- -Lys-OBut ( ; IV)

1

N- C- (. 7). , 1 2, (. 1). ±15° ±30°, ±90°, ±150°, sp3-sp2 . , 1, 2, . , , . II IV, , . 11- , - (. 1). , «» . , N- C- (. 4). , I III , - . , III, I, ~40% , 5 8.


1. Abel A. Advances in Amino Acid Mimetics and Peptidomimetics. Jai Press, Inc.: Greenwich, CT, 1997. 2. Schiller P.W., Nguyen T.M.D., Lemieux C., Maziak L.A. Synthesis and activity profiles of novel cyclic opioid peptide monomers and dimmers // J. Med Chem. 1985. v. 28. p. 1766-1771. 3. Schiller P.W., Nguyen T.M.D., Maziak L.A., Wilkes B.C. Lemieux C. Structure-activity relationships of cyclic opioid peptide analogues containing a phenylalanine residue in the 3-position // J. Med Chem. 1987. v. 30. p. 2094-2099. 4. Mierke D.F., Schiller P. W., Goodman M. A conformational comparison of two stereoisomeric cyclic dermorphin analogues employing NMR and computer simulations // Biopolymers 1990. v. 29. P. 943-952. 5. Fry D. C., Madison V. S., Greeley D. N., Felix A. M., Heimer E. P., Frohman L., Campbell R. M., Mowles T. F., Toome V,. Wegrzynski B. B. Solution structures of cyclic and dicyclic analogues of growth hormone releasing factor as determined by two-dimensional NMR and CD spectroscopies and constrained molecular dynamics // Biopolymers. 1992. v. 32. P. 649-666. 6. Charpentier B., Pelaprat D., Durieux C., Dor A., Reibaud M., Blanchard J. C., Roques B. P. Cyclic cholecystokinin analogues with high selectivity for central receptors // Proc Natl Acad Sci U S A. 1988. v. 85. P. 1968-1972. 7. Charpentier B., Dor A., Roy P., England P., Pham H., Durieux C., Roques B. P. Synthesis and binding affinities of cyclic and related linear analogues of CCK8 selective for central receptors // J Med Chem. 1989. v. 32. P. 1184-1190. 8. Roques B. P. Peptidomimetics as receptors agonists or peptidase inhibitors: a structural approach in the field of enkephalins, ANP and CCK // Biopolymers. 1992. V. 32. P. 407-410. 9. Al-Obeidi F., Castrucci A. M., Hadley M. E., Hruby V. J. Potent and prolonged acting cyclic lactam analogues of alpha-melanotropin: design based on molecular dynamics // J Med Chem. 1989. v. 32. P. 2555-2561. 10. Rao M. H., Yang W., Joshua H., Becker J. M., Naider F. Studies on conformational consequences of i to i + 3 side-chain cyclization in model cyclic tetrapeptides // Int J Pept Protein Res. 1995. v. 45. P. 418-429. 11. Holzemann G., Pachler K. G., Eberhart B., Holzel H., Kraft M., Barnickel G. Synthesis, conformational studies, and molecular dynamics calculations of two cyclic tetrapeptides with 17- and 18membered rings // Int J Pept Protein Res. 1991. v. 37. P. 283-92. 12. Schmidt R., Neubert K. Cyclization studies with tetra- and pentapeptide sequences corresponding to beta-casomorphins // Int J Pept Protein Res. 1991. v. 37. P. 502-507. 13. . ., . ., . ., . ., . . // . . 1990. . 16, . 358-369 14. Rone R., Manesis N., Hassan M., Goodman M. Conformational Analysis of Constrained Dilactambridged Tetrapeptides // Tetrahedron. 1988. v. 44. P. 895-924. 15. . ., . ., . ., . ., . . . // . . 1995. . 21. . 275-281. 16. Bitar K. G, Somogyvari-Vigh A., Coy D. H. Cyclic lactam analogues of ovine pituitary adenylate cyclase activating polypeptide (PACAP): discovery of potent type II receptor antagonists // Peptides. 1994. v. 15. v. 461-466. 17. Valero M. L., Camarero J. A., Adeva A., Verdaguer N., Fita I., Mateu M. G., Domingo E., Giralt E., Andreu D. Cyclic peptides as conformationally restricted models of viral antigens: application to foot-and-mouth disease virus // Biomed Pept Proteins Nucleic Acids. 1995. v. 1. P. 133-140.


18. Campbell R. M., Bongers J., Felix A. M. Rational design, synthesis, and biological evaluation of novel growth hormone releasing factor analogues // Biopolymers. 1995. v. 37. P. 67-88. 19. Schiller P. W., Nguyen T. M., Maziak L., Lemieux C. A novel cyclic opioid peptide analog showing high preference for mu-receptors // Biochem Biophys Res Commun. 1985. v. 127. P. 558-564. 20. Heavner G. A., Audhya T., Doyle D., Tjoeng F. S., Goldstein G. Biologically active conformations of thymopentin. Studies with conformationally restricted analogs // Int J Pept Protein Res. 1991. v. 37. P. 198-209. 21. . . . // . 2005. 22. . ., . . Asp Lys-Xaa // . 1997.. 62. . 879-885. 23. . ., . . Xaa-Asp // . . 1997.. 23. . 168-173. 24. . ., C. ., . ., . ., . ., . . - // . . 1997. . 23. . 531-538. 25. Brooks B. R., Bruccoleri R. E., Olafson B. D., States D. J., Swaminathan S., Karplus M. CHARMM: A Program for Macromolecular Energy, Minimization, and Dynamics Calculations.// J. Comp. Chem. 1983. v. 4. p. 187-217.

CONFORMATIONAL ANALYSIS OF CYCLIC DIPEPTIDES WITH NONSTANDARD GEOMETRY OF MOLECULAR SKELETON Arhipova S. F., Artemiev I. V., Goryacheva E. A., Pletnev V. Z. Conformational analysis of two pairs of synthetic cyclodipeptides formed via interaction of the side chain functional groups - Boc-Glu-Orn-OBut , Boc-Asp-Lys-OBut , as well as via those of the main and side chains ­ Boc-Glu- -Lys-OBut , Boc-Asp- -Lys-OBut has been performed by molecular mechanics method. The energy optimal conformational states of the molecules under study have been determined. It has been shown that conformational flexibility of molecular cyclic system depends on the relative position of the amide groups and the number of atoms in the cycle