Aziridide-based inhibitors of cathepsin L: Synthesis, inhibition activity, and docking studies

被引：55

作者：

Vicik, Radim

Busemann, Matthias

Gelhaus, Christoph

Stiefl, Nikolaus

Scheiber, Josef

Schmitz, Werner

Schulz, Franziska

Mladenovic, Milena

Engels, Bernd

Leippe, Matthias

Baumann, Knut

Schirmeister, Tanja

机构：

[1] Institute of Pharmacy and Food Chemistry, Department of Pharmaceutical/Medicinal Chemistry, University of Würzburg, 97074 Würzburg, Am Hubland

[2] Theodor Boveri Institute, Department of Physiological Chemistry II, University of Würzburg, 97074 Würzburg, Am Hubland

[3] Institute of Organic Chemistry, University of Würzburg, 97074 Würzburg, Am Hubland

[4] Zoological Institute, Department of Zoophysiology, University of Kiel, 24098 Kiel

[5] 4 SC AG

来源：

CHEMMEDCHEM | 2006年 / 1卷 / 10期

关键词：

Aziridines; Cathepsins; Cysteine proteases docking; Inhibitors;

D O I：

10.1002/cmdc.200600106

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A comprehensive screening of N-acylated aziridine (aziridide) based cysteine protease inhibitors containing either Boc-Leu-Caa (Caa=cyclic amino acid), Boc-Gly-Caa, or Boc-Phe-Ala attached to the aziridine nitrogen atom revealed Boc-(S)-Leu-(S)-Azy-(S,S)-Azi(OBn)(2) (18a) as a highly potent cathepsin L (CL) inhibitor (K(i) = 13 nm) (Azy = aziridine-2-carboxylate, Azi = aziridine-2,3-dicarboxylate). Docking studies, which also accounted for the unusual bonding situations (the flexibility and hybridization of the aziridides) predict that the inhibitor adopts a Y shape and spans across the entire active site cleft, binding into both the non-primed and primed sites of CL.

引用

页码：1126 / 1141

页数：16

共 42 条

[1]

AHLRICHS M, 1988, TURBOMOLE VERSIONS 5

[2]

[Anonymous], 1992, GRAFIT VERS 3 0

[3] DENSITY-FUNCTIONAL THERMOCHEMISTRY .3. THE ROLE OF EXACT EXCHANGE [J].

BECKE, AD .

JOURNAL OF CHEMICAL PHYSICS, 1993, 98 (07) :5648-5652

[4] DENSITY-FUNCTIONAL EXCHANGE-ENERGY APPROXIMATION WITH CORRECT ASYMPTOTIC-BEHAVIOR [J].

BECKE, AD .

PHYSICAL REVIEW A, 1988, 38 (06) :3098-3100

[5]

Bodansky M., 1984, PRACTICE PEPTIDE SYN, DOI 10.1007/978-3-642-96835-8

[6] An improved synthesis of aziridine-2,3-dicarboxylates via azido alcohols - epimerization studies [J].

Breuning, A ;

Vicik, R ;

Schirmeister, T .

TETRAHEDRON-ASYMMETRY, 2003, 14 (21) :3301-3312

[7] Design of noncovalent inhibitors of human cathepsin L.: From the 96-residue proregion to optimized tripeptides [J].

Chowdhury, SF ;

Sivaraman, J ;

Wang, J ;

Devanathan, G ;

Lachance, P ;

Qi, HT ;

Ménard, R ;

Lefebvre, J ;

Konishi, Y ;

Cygler, M ;

Sulea, T ;

Purisima, EO .

JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (24) :5321-5329

[8] AUXILIARY BASIS-SETS TO APPROXIMATE COULOMB POTENTIALS [J].

EICHKORN, K ;

TREUTLER, O ;

OHM, H ;

HASER, M ;

AHLRICHS, R .

CHEMICAL PHYSICS LETTERS, 1995, 240 (04) :283-289

[9] AUXILIARY BASIS-SETS TO APPROXIMATE COULOMB POTENTIALS (VOL 240, PG 283, 1995) [J].

EICHKORN, K ;

TREUTLER, O ;

OHM, H ;

HASER, M ;

AHLRICHS, R .

CHEMICAL PHYSICS LETTERS, 1995, 242 (06) :652-660

[10] Blocking effect of a biotinylated protease inhibitor on the egress of Plasmodium falciparum merozoites from infected red blood cells [J].

Gelhaus, C ;

Vicik, R ;

Schirmeister, T ;

Leippe, M .

BIOLOGICAL CHEMISTRY, 2005, 386 (05) :499-502

← 1 2 3 4 5 →