共查询到20条相似文献,搜索用时 31 毫秒
1.
Antonio Peón Dr. José M. Otero Lorena Tizón Verónica F. V. Prazeres Dr. Antonio L. Llamas‐Saiz Dr. Gavin C. Fox Dr. Mark J. van Raaij Dr. Heather Lamb Prof. Dr. Alastair R. Hawkins Prof. Dr. Federico Gago Prof. Dr. Luis Castedo Prof. Dr. Concepción González‐Bello 《ChemMedChem》2010,5(10):1726-1733
The binding mode of several substrate analogues, (2R)‐2‐benzyl‐3‐dehydroquinic acids 4 , which are potent reversible competitive inhibitors of type II dehydroquinase (DHQ2), the third enzyme of the shikimic acid pathway, has been investigated by structural and computational studies. The crystal structures of Mycobacterium tuberculosis and Helicobacter pylori DHQ2 in complex with one of the most potent inhibitor, p‐methoxybenzyl derivative 4 a , have been solved at 2.40 Å and 2.75 Å, respectively. This has allowed the resolution of the M. tuberculosis DHQ2 loop containing residues 20–25 for the first time. These structures show the key interactions of the aromatic ring in the active site of both enzymes and additionally reveal an important change in the conformation and flexibility of the loop that closes over substrate binding. The loop conformation and the binding mode of compounds 4 b – d has been also studied by molecular dynamics simulations, which suggest that the benzyl group of inhibitors 4 prevent appropriate orientation of the catalytic tyrosine of the loop for proton abstraction and disrupts its basicity. 相似文献
2.
Dr. Andrew J. Carnell Ralph Kirk Matthew Smith Shane McKenna Prof. Lu‐Yun Lian Dr. Robert Gibson 《ChemMedChem》2013,8(10):1643-1647
The enzyme α‐methylacyl CoA racemase (AMACR) is involved in the metabolism of branched‐chain fatty acids and has been identified as a promising therapeutic target for prostate cancer. By using the recently available human AMACR from HEK293 kidney cell cultures, we tested a series of new rationally designed inhibitors to determine the structural requirements in the acyl component. An N‐methylthiocarbamate (Ki=98 nM ), designed to mimic the proposed enzyme‐bound enolate, was found to be the most potent AMACR inhibitor reported to date. 相似文献
3.
Dr. Davide Bello Maria Grazia Rubanu Dr. Nouchali Bandaranayaka Dr. Jan P. Götze Prof. Dr. Michael Bühl Prof. Dr. David O'Hagan 《Chembiochem : a European journal of chemical biology》2019,20(9):1174-1182
In this study, we probed the inhibition of pig heart citrate synthase (E.C. 4.1.3.7) by synthesising seven analogues either designed to mimic the proposed enolate intermediate in this enzyme reaction or developed from historical inhibitors. The most potent inhibitor was fluorovinyl thioether 9 (Ki=4.3 μm ), in which a fluorine replaces the oxygen atom of the enolate. A comparison of the potency of 9 with that of its non-fluorinated vinyl thioether analogue 10 (Ki=68.3 μm ) revealed a clear “fluorine effect” favouring 9 by an order of magnitude. The dethia analogues of 9 and 10 proved to be poor inhibitors. A methyl sulfoxide analogue was a moderate inhibitor (Ki=11.1 μm ), thus suggesting hydrogen bonding interactions in the enolate site. Finally, E and Z propenoate thioether isomers were explored as conformationally constrained carboxylates, but these were not inhibitors. All compounds were prepared by the synthesis of the appropriate pantetheinyl diol and then assembly of the coenzyme A structure according to a three-enzyme biotransformation protocol. A quantum mechanical study, modelling both inhibitors 9 and 10 into the active site indicated short CF ⋅⋅⋅ H contacts of ≈2.0 Å, consistent with fluorine making two stabilising hydrogen bonds, and mimicking an enolate rather than an enol intermediate. Computation also indicated that binding of 9 to citrate synthase increases the basicity of a key aspartic acid carboxylate, which becomes protonated. 相似文献
4.
Dmytro Voskoboinyk Niusha Mahmoodi Chang Sheng-Huei Lin Michael E. P. Murphy Martin E. Tanner 《Chembiochem : a European journal of chemical biology》2023,24(11):e202300205
The O-acetylation of the muramic acid residues in peptidoglycan (PG) is a modification that protects the bacteria from lysis due to the action of lysozyme. In Gram-negative bacteria, deacetylation is required to allow lytic transglycosylases to promote PG cleavage during cell growth and division. This deacetylation is catalyzed by O-acetylpeptidoglycan esterase (Ape) which is a serine esterase and employs covalent catalysis via a serine-linked acyl enzyme intermediate. Loss of Ape activity affects the size and shape of bacteria and dramatically reduces virulence. In this work, we report the first rationally designed aldehyde-based inhibitors of Ape from Campylobacter jejuni. The most potent of these acts as a competitive inhibitor with a Ki value of 13 μM. We suspect that the inhibitors are forming adducts with the active site serine that closely mimic the tetrahedral intermediate of the normal catalytic cycle. Support for this notion is found in the observation that reduction of the aldehyde to an alcohol effectively abolishes the inhibition. 相似文献
5.
N‐Benzyl‐4‐((heteroaryl)methyl)benzamides: A New Class of Direct NADH‐Dependent 2‐trans Enoyl–Acyl Carrier Protein Reductase (InhA) Inhibitors with Antitubercular Activity 下载免费PDF全文
Ana Guardia Dr. Gulcin Gulten Dr. Raquel Fernandez Jesus Gómez Dr. Feng Wang Dr. Maire Convery Delia Blanco María Martínez Dr. Esther Pérez‐Herrán Marta Alonso Dr. Fátima Ortega Dr. Joaquín Rullás Dr. David Calvo Lydia Mata Dr. Robert Young Prof. James C. Sacchettini Dr. Alfonso Mendoza‐Losana Dr. Modesto Remuiñán Dr. Lluís Ballell Pages Dr. Julia Castro‐Pichel 《ChemMedChem》2016,11(7):687-701
Isoniazid (INH) remains one of the cornerstones of antitubercular chemotherapy for drug‐sensitive strains of M. tuberculosis bacteria. However, the increasing prevalence of multidrug‐resistant (MDR) and extensively drug‐resistant (XDR) strains containing mutations in the KatG enzyme, which is responsible for the activation of INH into its antitubercular form, have rendered this drug of little or no use in many cases of drug‐resistant tuberculosis. Presented herein is a novel family of antitubercular direct NADH‐dependent 2‐trans enoyl–acyl carrier protein reductase (InhA) inhibitors based on an N‐benzyl‐4‐((heteroaryl)methyl)benzamide template; unlike INH, these do not require prior activation by KatG. Given their direct InhA target engagement, these compounds should be able to circumvent KatG‐related resistance in the clinic. The lead molecules were shown to be potent inhibitors of InhA and showed activity against M. tuberculosis bacteria. This new family of inhibitors was found to be chemically tractable, as exemplified by the facile synthesis of analogues and the establishment of structure–activity relationships. Furthermore, a co‐crystal structure of the initial hit with the enzyme is disclosed, providing valuable information toward the design of new InhA inhibitors for the treatment of MDR/XDR tuberculosis. 相似文献
6.
He R Yu Z He Y Zeng LF Xu J Wu L Gunawan AM Wang L Jiang ZX Zhang ZY 《ChemMedChem》2010,5(12):2051-2056
Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), is a major worldwide threat to public health. Mycobacterium protein tyrosine phosphatase B (mPTPB) is a virulent phosphatase secreted by Mtb, which is essential for the survival and persistence of the bacterium in the host. Consequently, small‐molecule inhibitors of mPTPB are expected to serve as anti‐TB agents with a novel mode of action. Herein, we report the discovery of highly potent and selective mPTPB inhibitors using a novel, double Click chemistry strategy. The most potent mPTPB inhibitor from this approach possesses a Ki value of 160 nM and a >25‐fold selectivity for mPTPB over 19 other protein tyrosine phosphatases (PTBs). Molecular docking study of the enzyme–inhibitor complex provides a rationale for the high potency and selectivity of the lead compound and reveals an unusual binding mode, which may guide further optimization effort. 相似文献
7.
Douglas A. Kuntz Dr. Shinichi Nakayama Kayla Shea Hitoshi Hori Prof. Dr. Yoshihiro Uto Dr. Hideko Nagasawa Prof. Dr. David. R. Rose Prof. Dr. 《Chembiochem : a European journal of chemical biology》2010,11(5):673-680
Golgi α‐mannosidase II (GMII) is a key enzyme in the N‐glycosylation pathway and is a potential target for cancer chemotherapy. The natural product swainsonine is a potent inhibitor of GMII. In this paper we characterize the binding of 5α‐substituted swainsonine analogues to the soluble catalytic domain of Drosophila GMII by X‐ray crystallography. These inhibitors enjoy an advantage over previously reported GMII inhibitors in that they did not significantly decrease the inhibitory potential of the swainsonine head‐group. The phenyl groups of these analogues occupy a portion of the binding site not previously seen to be populated with either substrate analogues or other inhibitors and they form novel hydrophobic interactions. They displace a well‐organized water cluster, but the presence of a C(10) carbonyl allows the reestablishment of important hydrogen bonds. Already approximately tenfold more active against the Golgi enzyme than the lysosomal enzyme, these inhibitors offer the potential of being extended into the N‐acetylglucosamine binding site of GMII for the creation of even more potent and selective GMII inhibitors. 相似文献
8.
Dr. Isabell Walter Dr. Sebastian Adam Dr. Maria Virginia Gentilini Dr. Andreas M. Kany Dr. Christian Brengel Dr. Andreas Thomann Prof. Dr. Tim Sparwasser Dr. Jesko Köhnke Prof. Dr. Rolf W. Hartmann 《ChemMedChem》2021,16(18):2786-2801
CYP121 of Mycobacterium tuberculosis (Mtb) is an essential target for the development of novel potent drugs against tuberculosis (TB). Besides known antifungal azoles, further compounds of the azole class were recently identified as CYP121 inhibitors with antimycobacterial activity. Herein, we report the screening of a similarity-oriented library based on the former hit compound, the evaluation of affinity toward CYP121, and activity against M. bovis BCG. The results enabled a comprehensive SAR study, which was extended through the synthesis of promising compounds and led to the identification of favorable features for affinity and/or activity and hit compounds with 2.7-fold improved potency. Mode of action studies show that the hit compounds inhibit substrate conversion and highlighted CYP121 as the main antimycobacterial target of our compounds. Exemplified complex crystal structures of CYP121 with three inhibitors reveal a common binding site. Engaging in both hydrophobic interactions as well as hydrogen bonding to the sixth iron ligand, our compounds block a solvent channel leading to the active site heme. Additionally, we report the first CYP inhibitors that are able to reduce the intracellular replication of M. bovis BCG in macrophages, emphasizing their potential as future drug candidates against TB. 相似文献
9.
Design and Structural Analysis of Aromatic Inhibitors of Type II Dehydroquinase from Mycobacterium tuberculosis 下载免费PDF全文
Dr. Nigel I. Howard Dr. Marcio V. B. Dias Dr. Fabienne Peyrot Dr. Liuhong Chen Dr. Marco F. Schmidt Prof. Tom L. Blundell Prof. Chris Abell 《ChemMedChem》2015,10(1):116-133
3‐Dehydroquinase, the third enzyme in the shikimate pathway, is a potential target for drugs against tuberculosis. Whilst a number of potent inhibitors of the Mycobacterium tuberculosis enzyme based on a 3‐dehydroquinate core have been identified, they generally show little or no in vivo activity, and were synthetically complex to prepare. This report describes studies to develop tractable and drug‐like aromatic analogues of the most potent inhibitors. A range of carbon–carbon linked biaryl analogues were prepared to investigate the effect of hydrogen bond acceptor and donor patterns on inhibition. These exhibited inhibitory activity in the high‐micromolar range. The addition of flexible linkers in the compounds led to the identification of more potent 3‐nitrobenzylgallate‐ and 5‐aminoisophthalate‐based analogues. 相似文献
10.
Julie G. Geist Susan Lauw Dr. Victoria Illarionova Dr. Boris Illarionov Dr. Markus Fischer Prof. Dr. Tobias Gräwert Dr. Felix Rohdich Dr. Wolfgang Eisenreich Dr. Johannes Kaiser Dr. Michael Groll Prof. Dr. Christian Scheurer Sergio Wittlin Dr. José L. Alonso‐Gómez Dr. W. Bernd Schweizer Dr. Adelbert Bacher Prof. Dr. François Diederich Prof. Dr. 《ChemMedChem》2010,5(7):1092-1101
A library of 40 000 compounds was screened for inhibitors of 2‐methylerythritol 2,4‐cyclodiphosphate synthase (IspF) protein from Arabidopsis thaliana using a photometric assay. A thiazolopyrimidine derivative resulting from the high‐throughput screen was found to inhibit the IspF proteins of Mycobacterium tuberculosis, Plasmodium falciparum, and A. thaliana with IC50 values in the micromolar range. Synthetic efforts afforded derivatives that inhibit IspF protein from M. tuberculosis and P. falciparum with IC50 values in the low micromolar range. Several compounds act as weak inhibitors in the P. falciparum red blood cell assay. 相似文献
11.
Inhibitors of the salicylate synthase (MbtI) from Mycobacterium tuberculosis discovered by high-throughput screening 总被引:1,自引:0,他引:1
Vasan M Neres J Williams J Wilson DJ Teitelbaum AM Remmel RP Aldrich CC 《ChemMedChem》2010,5(12):2079-2087
A simple steady‐state kinetic high‐throughput assay was developed for the salicylate synthase MbtI from Mycobacterium tuberculosis, which catalyzes the first committed step of mycobactin biosynthesis. The mycobactins are small‐molecule iron chelators produced by M. tuberculosis, and their biosynthesis has been identified as a promising target for the development of new antitubercular agents. The assay was miniaturized to a 384‐well plate format and high‐throughput screening was performed at the National Screening Laboratory for the Regional Centers of Excellence in Biodefense and Emerging Infectious Diseases (NSRB). Three classes of compounds were identified comprising the benzisothiazolones (class I), diarylsulfones (class II), and benzimidazole‐2‐thiones (class III). Each of these compound series was further pursued to investigate their biochemical mechanism and structure–activity relationships. Benzimidazole‐2‐thione 4 emerged as the most promising inhibitor owing to its potent reversible inhibition. 相似文献
12.
Synthesis and Structure–Activity Relationship Studies of 2‐(1,3,4‐Oxadiazole‐2(3H)‐thione)‐3‐amino‐5‐arylthieno[2,3‐b]pyridines as Inhibitors of DRAK2 下载免费PDF全文
Dr. Piotr Leonczak Dr. Ling‐Jie Gao Dr. Anna Teresa Ramadori Prof. Eveline Lescrinier Prof. Jef Rozenski Dr. Steven De Jonghe Prof. Piet Herdewijn 《ChemMedChem》2014,9(11):2587-2601
In recent years, DAPK‐related apoptosis‐inducing protein kinase 2 (DRAK2) has emerged as a promising target for the treatment of a variety of autoimmune diseases and for the prevention of graft rejection after organ transplantation. However, medicinal chemistry optimization campaigns for the discovery of novel small‐molecule inhibitors of DRAK2 have not yet been published. Screening of a proprietary compound library led to the discovery of a benzothiophene analogue that displays an affinity constant (Kd) value of 0.25 μM . Variation of the core scaffold and of the substitution pattern afforded a series of 5‐arylthieno[2,3‐b]pyridines with strong binding affinity (Kd=0.008 μM for the most potent representative). These compounds also show promising activity in a functional biochemical DRAK2 enzyme assay, with an IC50 value of 0.029 μM for the most potent congener. Selectivity profiling of the most potent compounds revealed that they lack selectivity within the DAPK family of kinases. However, one of the less potent analogues is a selective ligand for DRAK2 and can be used as starting point for the synthesis of selective and potent DRAK2 inhibitors. 相似文献
13.
Single‐Turnover Kinetics Reveal a Distinct Mode of Thiamine Diphosphate‐Dependent Catalysis in Vitamin K Biosynthesis 下载免费PDF全文
Mingming Qin Dr. Haigang Song Xin Dai Chi‐Kong Chan Prof. Wan Chan Prof. Dr. Zhihong Guo 《Chembiochem : a European journal of chemical biology》2018,19(14):1514-1522
MenD, or (1R,2S,5S,6S)‐2‐succinyl‐5‐enolpyruvyl‐6‐hydroxycyclohex‐3‐ene‐1‐carboxylate (SEPHCHC) synthase, uses a thiamine diphosphate (ThDP)‐dependent tetrahedral Breslow intermediate rather than a canonical enamine for catalysis in the biosynthesis of vitamin K. By real‐time monitoring of the cofactor chemical state with circular dichroism spectroscopy, we found that a new post‐decarboxylation intermediate was formed from a multistep process that was rate limited by binding of the α‐ketoglutarate substrate before it quickly relaxed to the characterized tetrahedral Breslow intermediate. In addition, the chemical steps leading to the reactive post‐decarboxylation intermediates were not affected by the electrophilic substrate, isochorismate, whereas release of the product was found to limit the whole catalytic process. Moreover, these intermediates are likely kinetically stabilized owing to the low biological availability of isochorismate under physiological conditions, in contrast to the tight coupling of enamine formation with binding of the electrophilic acceptor in some other ThDP‐dependent enzymes. Together with the unusual tetrahedral structure of the intermediates, these findings strongly support a new ThDP‐dependent catalytic mode distinct from canonical enamine chemistry. 相似文献
14.
Alain Rahier Maryse Taton Pierrette Bouvier-Navé Paulette Schmitt Pierre Benveniste Francis Schuber Acharan S. Narula Luigi Cattel Claude Anding Pierre Place 《Lipids》1986,21(1):52-62
Several enzymes of plant sterol biosynthesis involve during their catalysis postulated or demonstrated carbocationic high
energy intermediates (HEI). The aim of this study was to interfere with plant sterol biosynthesis by means of rationally designed
species able to mimic these carbocationic HEI. It has been demonstrated previously that the design of transition state (TS)
or HEI analogues could lead to powerful and specific inhibitors of enzymes. We applied this approach to the following target
enzymes: 2,3-epoxy-2,3-dihydroqualene cyclase, AdoMet-cycloartenol-C-24-methyltransferase (AdoMet CMT), cycloeucalenol-obtusifoliol
isomerase (COI) and Δ8-Δ7-sterol isomerase. Very potent inhibitors have been obtained in the four cases. As an example, analogues of cycloartenol substituted
at C-25 by a charged heteroatom (N, As, S) have been synthesized and shown to be able to mimic the C-25 carbocationic HEI
involved in the reaction catalyzed by the AdoMet CMT. These compounds were shown to be very potent and specific inhibitors
of this enzyme both in vitro (Ki=2.10−8 M, Ki/Km=10−3) and in vivo. The potent inhibitors described are powerful tools to control in vivo the sterol profile of plant cells and
therefore to study the structural and functional roles of sterols in cell membranes. Moreover, these compounds constitute
leader molecules of a new class of rationally designed inhibitors which could be of value in plant protection. 相似文献
15.
A H M Renfrew I Bates D A S Phillips T Rosenau T Tomic J Xu 《Coloration Technology》2008,124(1):56-61
A new water‐soluble monomeric agent for the aminisation of lyocell has been designed and synthesised. The agent, which contains a sulphatoethylsulphonyl group, an s‐triazinyl keto–enol tautomeric system and a primary aromatic amine was prepared in acidic media, in good yield from cyanuric chloride, p‐aminophenyl‐β‐sulphatoethylsulphone and p‐phenylenediamine, via a triazinyl betaine intermediate. 相似文献
16.
Recent reports document that α‐tetralone (3,4‐dihydro‐2H‐naphthalen‐1‐one) is an appropriate scaffold for the design of high‐potency monoamine oxidase (MAO) inhibitors. Based on the structural similarity between α‐tetralone and 1‐indanone, the present study involved synthesis of 34 1‐indanone and related indane derivatives as potential inhibitors of recombinant human MAO‐A and MAO‐B. The results show that C6‐substituted indanones are particularly potent and selective MAO‐B inhibitors, with IC50 values ranging from 0.001 to 0.030 μM . C5‐Substituted indanone and indane derivatives are comparatively weaker MAO‐B inhibitors. Although the 1‐indanone and indane derivatives are selective inhibitors of the MAO‐B isoform, a number of homologues are also potent MAO‐A inhibitors, with three homologues possessing IC50 values <0.1 μM . Dialysis of enzyme–inhibitor mixtures further established a selected 1‐indanone as a reversible MAO inhibitor with a competitive mode of inhibition. It may be concluded that 1‐indanones are promising leads for the design of therapies for neurodegenerative and neuropsychiatric disorders such as Parkinson’s disease and depression. 相似文献
17.
Synthesis,Biochemistry, and Computational Studies of Brominated Thienyl Chalcones: A New Class of Reversible MAO‐B Inhibitors 下载免费PDF全文
Bijo Mathew Abitha Haridas Prof. Dr. Gülberk Uçar Ipek Baysal Monu Joy Githa E. Mathew Dr. Baskar Lakshmanan Dr. Venkatesan Jayaprakash 《ChemMedChem》2016,11(11):1161-1171
A series of (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(para‐substituted phenyl)prop‐2‐en‐1‐ones ( TB1 – TB11 ) was synthesized and tested for inhibitory activity toward human monoamine oxidase (hMAO). All compounds were found to be competitive, selective, and reversible toward hMAO‐B except (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(4‐nitrophenyl)prop‐2‐en‐1‐one ( TB7 ) and (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(4‐chlorophenyl)prop‐2‐en‐1‐one ( TB8 ), which were selective inhibitors of hMAO‐A. The most potent compound, (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐[4‐(dimethylamino)phenyl]prop‐2‐en‐1‐one ( TB5 ), showed the best inhibitory activity and higher selectivity toward hMAO‐B, with Ki and SI values of 0.11±0.01 μm and 13.18, respectively. PAMPA assays for all compounds were carried out in order to evaluate the capacity of the compounds to cross the blood–brain barrier. Moreover, the most potent MAO‐B inhibitor, TB5 , was found to be nontoxic at 5 and 25 μm , with 95.75 and 84.59 % viability among cells, respectively. Molecular docking simulations were carried out to understand the crucial interactions responsible for selectivity and potency. 相似文献
18.
Prazeres VF Sánchez-Sixto C Castedo L Lamb H Hawkins AR Riboldi-Tunnicliffe A Coggins JR Lapthorn AJ González-Bello C 《ChemMedChem》2007,2(2):194-207
Isomeric nitrophenyl and heterocyclic analogues of the known inhibitor (1S,3R,4R)-1,3,4-trihydroxy-5-cyclohexene-1-carboxylic acid have been synthesized and tested as inhibitors of M. tuberculosis and S. coelicolor type II dehydroquinase, the third enzyme of the shikimic acid pathway. The target compounds were synthesized by a combination of Suzuki and Sonogashira cross-coupling and copper(I)-catalyzed 2,3-dipolar cycloaddition reactions from a common vinyl triflate intermediate. These studies showed that a para-nitrophenyl derivative is almost 20-fold more potent as a competitive inhibitor against the S. coelicolor enzyme than that of M. tuberculosis. The opposite results were obtained with the meta isomer. Five of the bicyclic analogues reported herein proved to be potent competitive inhibitors of S. coelicolor dehydroquinase, with inhibition constants in the low nanomolar range (4-30 nM). These derivatives are also competitive inhibitors of the M. tuberculosis enzyme, but with lower affinities. The most potent inhibitor against the S. coelicolor enzyme, a 6-benzothiophenyl derivative, has a K(i) value of 4 nM-over 2000-fold more potent than the best previously known inhibitor, (1R,4R,5R)-1,5-dihydroxy-4-(2-nitrophenyl)cyclohex-2-en-1-carboxylic acid (8 microM), making it the most potent known inhibitor against any dehydroquinase. The binding modes of the analogues in the active site of the S. coelicolor enzyme (GOLD 3.0.1), suggest a key pi-stacking interaction between the aromatic rings and Tyr 28, a residue that has been identified as essential for enzyme activity. 相似文献
19.
Janina Schmitz Norbert Furtmann Moritz Ponert Dr. Maxim Frizler Dr. Reik Löser Prof. Dr. Ulrike Bartz Prof. Dr. Jürgen Bajorath Prof. Dr. Michael Gütschow 《ChemMedChem》2015,10(8):1365-1377
Cleavage of the invariant chain is the key event in the trafficking pathway of major histocompatibility complex class II. Cathepsin S is the major processing enzyme of the invariant chain, but cathepsin F acts in macrophages as its functional synergist which is as potent as cathepsin S in invariant chain cleavage. Dedicated low‐molecular‐weight inhibitors for cathepsin F have not yet been developed. An active site mapping with 52 dipeptide nitriles, reacting as covalent–reversible inhibitors, was performed to draw structure–activity relationships for the non‐primed binding region of human cathepsin F. In a stepwise process, new compounds with optimized fragment combinations were designed and synthesized. These dipeptide nitriles were evaluated on human cysteine cathepsins F, B, L, K and S. Compounds 10 (N‐(4‐phenylbenzoyl)‐leucylglycine nitrile) and 12 (N‐(4‐phenylbenzoyl)leucylmethionine nitrile) were found to be potent inhibitors of human cathepsin F, with Ki values <10 nM . With all dipeptide nitriles from our study, a 3D activity landscape was generated to visualize structure–activity relationships for this series of cathepsin F inhibitors. 相似文献
20.
Bai Y Ling Y Shi W Cai L Jia Q Jiang S Liu K 《Chembiochem : a European journal of chemical biology》2011,12(17):2647-2658
Enzyme efficiency results from the cooperation of functional groups in the catalytic site. In order to mimic a natural enzyme, a definite 3D scaffold must be carefully designed so that the functional groups can work cooperatively. During the HIV‐1 fusion process, the gp41 N‐ and C‐terminal heptad repeat regions form a coiled‐coil six‐helical bundle (6HB) that brings the viral and target cell membranes into close proximity for fusion. We used 6HB as the molecular model for a novel scaffold for the design of an artificial enzyme, in which the modified C34 and N36 peptides formed a unique 6HB structure through specific molecular recognition, and the position and orientation of the side‐chain groups on this scaffold were predictable. The histidine modified 6HB C34H13/20/N36H15/22 showed enzyme‐like hydrolytic activity towards p‐nitrophenyl acetate (PNPA; kcat/KM=3.66 M ?1 s?1) through the cooperation of several inter‐ or intrahelical imidazole groups. Since the catalytic activity of 6HB depends on the C‐ and N‐peptide assembly, either HIV fusion inhibitors that can compete with the formation of catalytic 6HB or denaturants that can destroy the ordered structure were able to modulate its activity. Further engineering of the solvent‐exposing face with Glu?‐Lys+ salt bridges enhanced the helicity and the stability of 6HB. As a result, the population and stability of cooperative catalytic units increased. In addition, the Glu?‐Lys+‐stabilized 6HB SC35H13/20/N36H15/22 had increased catalytic efficiency (kcat/KM=6.30 M ?1 s?1). A unique 6HB system was specifically assembled and provided a scaffold sufficiently stable to mimic the function of enzymes or other biomolecules. 相似文献