Virtual Screening and Computational Optimization for the Discovery of Covalent Prolyl Oligopeptidase Inhibitors with Activity in Human Cells

被引：46

作者：

De Cesco, Stephane ^{[1
]}

Deslandes, Sebastien ^{[1
]}

Therrien, Eric ^{[1
]}

Levan, David ^{[1
]}

Cueto, Mickael ^{[1
]}

Schmidt, Ralf ^{[2
]}

Cantin, Louis-David ^{[2
]}

Mittermaier, Anthony ^{[1
]}

Juilerat-Jeanneret, Lucienne ^{[3
]}

Moitessier, Nicolas ^{[1
]}

机构：

[1] McGill Univ, Dept Chem, Montreal, PQ H3A 0B8, Canada

[2] AstraZeneca R&D, St Laurent, PQ H4S 1Z9, Canada

[3] CHUV UNIL, Univ Inst Pathol, CH-1011 Lausanne, Switzerland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 14期

基金：

加拿大自然科学与工程研究理事会;

关键词：

ENDOPEPTIDASE INHIBITOR; SOLVATED MACROMOLECULES; DOCKING LIGANDS; JTP-4819; PEPTIDASE; FORMS;

D O I：

10.1021/jm3002839

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Our docking program, Fitted, implemented in our computational platform, Forecaster, has been modified to carry out automated virtual screening of covalent inhibitors. With this modified version of the program, virtual screening and further docking-based optimization of a selected hit led to the identification of potential covalent reversible inhibitors of prolyl oligopeptidase activity. After visual inspection, a virtual hit molecule together with four analogues were selected for synthesis and made in one five chemical steps. Biological evaluations on recombinant POP and FAP alpha enzymes, cell extracts, and living cells demonstrated high potency and selectivity for POP over FAP alpha and DPPIV. Three compounds even exhibited high nanomolar inhibitory activities in intact living human cells and acceptable metabolic stability. This small set of molecules also demonstrated that covalent binding and/or geometrical constraints to the ligand/protein complex may lead to an increase in bioactivity.

引用

页码：6306 / 6315

页数：10

共 43 条

[11] Unsupervised guided docking of covalently bound ligands [J].

Fradera, X ;

Kaur, J ;

Mestres, J .

JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 2004, 18 (10) :635-650

[12] Prolyl oligopeptidase:: An unusual β-propeller domain regulates proteolysis [J].

Fülöp, V ;

Böcskei, Z ;

Polgár, L .

CELL, 1998, 94 (02) :161-170

[13] Distribution of prolyl endopeptidase activities in rat and human brain [J].

Irazusta, J ;

Larrinaga, G ;

González-Maeso, J ;

Gil, J ;

Meana, JJ ;

Casis, L .

NEUROCHEMISTRY INTERNATIONAL, 2002, 40 (04) :337-345

[14] ZINC - A free database of commercially available compounds for virtual screening [J].

Irwin, JJ ;

Shoichet, BK .

JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2005, 45 (01) :177-182

[15] Brain Pharmacokinetics of Two Prolyl Oligopeptidase Inhibitors, JTP-4819 and KYP-2047, in the Rat [J].

Jalkanen, Aaro J. ;

Hakkarainen, Jenni J. ;

Lehtonen, Marko ;

Venalainen, Tetta ;

Kaariainen, Tiina M. ;

Jarho, Elina ;

Suhonen, Marjukka ;

Forsberg, Markus M. .

BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY, 2011, 109 (06) :443-451

[16]

Juillerat-Jeanneret L., 2008, CURR CHEM BIOL, V2, P97

[17] Benzyloxycarbonylprolylprolinal, a transition-state analogue for prolyl oligopeptidase, forms a tetrahedral adduct with catalytic serine, not a reactive cysteine [J].

Kahyaoglu, A ;

Haghjoo, K ;

Kraicsovits, F ;

Jordan, F ;

Polgar, L .

BIOCHEMICAL JOURNAL, 1997, 322 :839-843

[18] Molecular dynamics, crystallography and mutagenesis studies on the substrate gating mechanism of prolyl oligopeptidase [J].

Kaszuba, Karol ;

Rog, Tomasz ;

Danne, Reinis ;

Canning, Peter ;

Fueloep, Vilmos ;

Juhasz, Tuende ;

Szeltner, Zoltan ;

St Pierre, J. -F. ;

Garcia-Horsman, Arturo ;

Mannisto, Pekka T. ;

Karttunen, Mikko ;

Hokkanen, Jyrki ;

Bunker, Alex .

BIOCHIMIE, 2012, 94 (06) :1398-1411

[19]

Kato A, 1997, J PHARMACOL EXP THER, V283, P328

[20] Discovery of small molecule inhibitors of ubiquitin-like poxvirus proteinase I7L using homology modeling and covalent docking approaches [J].

Katritch, Vsevolod ;

Byrd, Chelsea M. ;

Tseitin, Vladimir ;

Dai, Dongcheng ;

Raush, Eugene ;

Totrov, Maxim ;

Abagyan, Ruben ;

Jordan, Robert ;

Hruby, Dennis E. .

JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 2007, 21 (10-11) :549-558

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