STRUCTURE-BASED DESIGN OF AN INHIBITOR OF THE ZINC PEPTIDASE THERMOLYSIN

被引:42
作者
MORGAN, BP
HOLLAND, DR
MATTHEWS, BW
BARTLETT, PA
机构
[1] UNIV CALIF BERKELEY, DEPT CHEM, BERKELEY, CA 94720 USA
[2] UNIV OREGON, INST MOLEC BIOL, EUGENE, OR 97403 USA
[3] UNIV OREGON, HOWARD HUGHES MED INST, EUGENE, OR 97403 USA
关键词
D O I
10.1021/ja00087a010
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The full cycle of design, synthesis, and enzymatic and crystallographic evaluation of a structure-based inhibitor of thermolysin is described. Using the structure of the complex of thermolysin with Cbz-Gly(P)-Leu-Leu (K-i = 9 nM; ''Gly(P)'' = NHCH2PO2-) as the starting point, we designed the macrocyclic phosphonamidate (S,S)-1 as a conformationally constrained derivative. The chroman linking unit was designed to rigidify the peptide analog while avoiding unfavorable steric interactions with the enzyme. (S,S)-1 was synthesized by a route that provided all of the stereoisomers in pure form; the acyclic control compounds 2 and 3 were also prepared. The binding affinity of (S,S)-1 (K-i = 4 nM) is enhanced by 2.3 kcal/mol in comparison to 3 (K-i = 190 nM); the other diastereomers of 1 are considerably less potent (K-i greater than or equal to 500 nM). Crystallographic analysis of the complexes between thermolysin and (S,S)-1 and (S)-2 demonstrated that the anticipated mode of binding of (S,S)-1 was fundamentally correct, while revealing some discrepancies with the original model. The structural studies also showed that the chroman moiety in the acyclic analog (S)-2 binds in a different orientation than in the macrocycle, an observation that is important for interpreting the differences in affinity between the macrocyclic inhibitor and the control compounds.
引用
收藏
页码:3251 / 3260
页数:10
相关论文
共 96 条
[1]   THIENOTHIOPYRAN-2-SULFONAMIDES - NOVEL TOPICALLY ACTIVE CARBONIC-ANHYDRASE INHIBITORS FOR THE TREATMENT OF GLAUCOMA [J].
BALDWIN, JJ ;
PONTICELLO, GS ;
ANDERSON, PS ;
CHRISTY, ME ;
MURCKO, MA ;
RANDALL, WC ;
SCHWAM, H ;
SUGRUE, MF ;
SPRINGER, JP ;
GAUTHERON, P ;
GROVE, J ;
MALLORGA, P ;
VIADER, MP ;
MCKEEVER, BM ;
NAVIA, MA .
JOURNAL OF MEDICINAL CHEMISTRY, 1989, 32 (12) :2510-2513
[2]   POSSIBLE ROLE FOR WATER DISSOCIATION IN THE SLOW BINDING OF PHOSPHORUS-CONTAINING TRANSITION-STATE-ANALOGUE INHIBITORS OF THERMOLYSIN [J].
BARTLETT, PA ;
MARLOWE, CK .
BIOCHEMISTRY, 1987, 26 (26) :8553-8561
[3]   PHOSPHONAMIDATES AS TRANSITION-STATE ANALOG INHIBITORS OF THERMOLYSIN [J].
BARTLETT, PA ;
MARLOWE, CK .
BIOCHEMISTRY, 1983, 22 (20) :4618-4624
[4]  
BARTLETT PA, 1989, USE XRAY CRYSTALLOGR
[5]   ADDITIVITY RULES FOR ESTIMATION OF THERMOCHEMICAL PROPERTIES [J].
BENSON, SW ;
CRUICKSHANK, FR ;
GOLDEN, DM ;
HAUGEN, GR ;
ONEAL, HE ;
RODGERS, AS ;
SHAW, R ;
WALSH, R .
CHEMICAL REVIEWS, 1969, 69 (03) :279-+
[6]  
BERNSTEIN FL, 1977, J MOL BIOL, V185, P535
[7]   COMPUTER-GRAPHICS IN DRUG DESIGN - MOLECULAR MODELING OF THYROID-HORMONE PRE-ALBUMIN INTERACTIONS [J].
BLANEY, JM ;
JORGENSEN, EC ;
CONNOLLY, ML ;
FERRIN, TE ;
LANGRIDGE, R ;
OATLEY, SJ ;
BURRIDGE, JM ;
BLAKE, CCF .
JOURNAL OF MEDICINAL CHEMISTRY, 1982, 25 (07) :785-790
[8]   SELECTION OF COHERENCE-TRANSFER PATHWAYS IN NMR PULSE EXPERIMENTS [J].
BODENHAUSEN, G ;
KOGLER, H ;
ERNST, RR .
JOURNAL OF MAGNETIC RESONANCE, 1984, 58 (03) :370-388
[9]   OXYGEN HETEROCYCLES BY THE PARHAM CYCLIALKYLATION [J].
BRADSHER, CK ;
REAMES, DC .
JOURNAL OF ORGANIC CHEMISTRY, 1981, 46 (07) :1384-1388
[10]   LARGE-SCALE SYNTHESIS OF A CYCLIC HEXAPEPTIDE ANALOG OF SOMATOSTATIN [J].
BRADY, SF ;
FREIDINGER, RM ;
PALEVEDA, WJ ;
COLTON, CD ;
HOMNICK, CF ;
WHITTER, WL ;
CURLEY, P ;
NUTT, RF ;
VEBER, DF .
JOURNAL OF ORGANIC CHEMISTRY, 1987, 52 (05) :764-769