An old target revisited:: Two new privileged skeletons and an unexpected binding mode for HIV-protease inhibitors

被引：35

作者：

Specker, E

Böttcher, J

Lilie, H

Heine, A

Schoop, A

Müller, G

Griebenow, N

Klebe, G

机构：

[1] Univ Marburg, Inst Pharmazeut Chem, D-35032 Marburg, Germany

[2] Univ Halle Wittenberg, Inst Biotechnol, D-06120 Halle An Der Saale, Germany

[3] Boehringer Ingelheim GmbH & Co KG, Vienna, Austria

[4] Axxima Pharmaceut AG, Munich, Germany

[5] Bayer AG, Elberfeld, Germany

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2005年 / 44卷 / 20期

关键词：

drug design; HIV protease; inhibitors; proteins; structure determination;

D O I：

10.1002/anie.200462643

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Favored entrance for the privileged. Two inhibitor structures to address the active site of aspartic proteases have been developed. They are equipped with a central hydroxysulfone unit and, alternatively, a pyrrolidine moiety and decorated with rationally designed side chains. The hydroxysulfones bind to HIV protease as expected, whereas the pyrrolidines display a surprising, previously unreported binding mode. (Chemical Equation Presented) © 2005 Wiley-VCH Verlag GmbH & Co. KGaA.

引用

收藏

页码：3140 / 3144

页数：5

相关论文

共 16 条

[1] Molecular recognition of protein-ligand complexes: Applications to drug design [J].

Babine, RE ;

Bender, SL .

CHEMICAL REVIEWS, 1997, 97 (05) :1359-1472

[2] CRYSTAL-STRUCTURES OF NATIVE AND INHIBITED FORMS OF HUMAN CATHEPSIN-D - IMPLICATIONS FOR LYSOSOMAL TARGETING AND DRUG DESIGN [J].

BALDWIN, ET ;

BHAT, TN ;

GULNIK, S ;

HOSUR, MV ;

SOWDER, RC ;

CACHAU, RE ;

COLLINS, J ;

SILVA, AM ;

ERICKSON, JW .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (14) :6796-6800

[3] 2′,6′-dimethylphenoxyacetyl:: A new achiral high affinity P3-P2 ligand for peptidomimetic-based HIV protease inhibitors [J].

Beaulieu, PL ;

Anderson, PC ;

Cameron, DR ;

Croteau, G ;

Gorys, V ;

Grand-Maitre, C ;

Lamarre, D ;

Liard, F ;

Paris, W ;

Plamondon, L ;

Soucy, F ;

Thibeault, D ;

Wernic, D ;

Yoakim, C ;

Pav, S ;

Tong, L .

JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (06) :1094-1108

[4] RENIN INHIBITORS - DIPEPTIDE ANALOGS OF ANGIOTENSINOGEN INCORPORATING TRANSITION-STATE, NONPEPTIDIC REPLACEMENTS AT THE SCISSILE BOND [J].

BOLIS, G ;

FUNG, AKL ;

GREER, J ;

KLEINERT, HD ;

MARCOTTE, PA ;

PERUN, TJ ;

PLATTNER, JJ ;

STEIN, HH .

JOURNAL OF MEDICINAL CHEMISTRY, 1987, 30 (10) :1729-1737

[5] HIV-1 protease: mechanism and drug discovery [J].

Brik, A ;

Wong, CH .

ORGANIC & BIOMOLECULAR CHEMISTRY, 2003, 1 (01) :5-14

[6] ANALYTICAL MOLECULAR-SURFACE CALCULATION [J].

CONNOLLY, ML .

JOURNAL OF APPLIED CRYSTALLOGRAPHY, 1983, 16 (OCT) :548-558

[7] HIV-chemotherapy and -prophylaxis: new drugs, leads and approaches [J].

De Clercq, E .

INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 2004, 36 (09) :1800-1822

[8]

FITZGERALD PMD, 1990, J BIOL CHEM, V265, P14209

[9] Structure-based design:: Potent inhibitors of human brain memapsin 2 (β-secretase) [J].

Ghosh, AK ;

Bilcer, G ;

Harwood, C ;

Kawahama, R ;

Shin, D ;

Hussain, KA ;

Hong, L ;

Loy, JA ;

Nguyen, C ;

Koelsch, G ;

Ermolieff, J ;

Tang, J .

JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (18) :2865-2868

[10] CRYSTAL-STRUCTURE OF HIV-1 PROTEASE IN COMPLEX WITH VX-478, A POTENT AND ORALLY BIOAVAILABLE INHIBITOR OF THE ENZYME [J].

KIM, EE ;

BAKER, CT ;

DWYER, MD ;

MURCKO, MA ;

RAO, BG ;

TUNG, RD ;

NAVIA, MA .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1995, 117 (03) :1181-1182