共查询到20条相似文献,搜索用时 296 毫秒
1.
Lovejoy B Welch AR Carr S Luong C Broka C Hendricks RT Campbell JA Walker KA Martin R Van Wart H Browner MF 《Nature structural biology》1999,6(3):217-221
The X-ray crystal structures of the catalytic domain of human collagenase-3 (MMP-13) and collagenase-1 (MMP-1) with bound inhibitors provides a basis for understanding the selectivity profile of a novel series of matrix metalloprotease (MMP) inhibitors. Differences in the relative size and shape of the MMP S1' pockets suggest that this pocket is a critical determinant of MMP inhibitor selectivity. The collagenase-3 S1' pocket is long and open, easily accommodating large P1' groups, such as diphenylether. In contrast, the collagenase-1 S1' pocket must undergo a conformational change to accommodate comparable P1' groups. The selectivity of the diphenylether series of inhibitors for collagenase-3 is largely determined by their affinity for the preformed S1' pocket of collagenase-3, as compared to the induced fit in collagenase-1. 相似文献
2.
J Holms K Mast P Marcotte I Elmore J Li L Pease K Glaser D Morgan M Michaelides S Davidsen 《Bioorganic & medicinal chemistry letters》2001,11(22):2907-2910
Modification of the P(1)' substituent of macrocyclic matrix metalloproteinase (MMP) inhibitors provided compounds that are selective for inhibition of tumor necrosis factor-alpha converting enzyme (TACE) over MMP-1 and MMP-2. Several analogues potently inhibited the release of TNF-alpha in a THP-1 cellular assay. Compounds containing a trimethoxyphenyl group in the P(1)' substituent demonstrated TACE selectivity across several series of hydroxamate-based inhibitors. 相似文献
3.
Dunten P Kammlott U Crowther R Levin W Foley LH Wang P Palermo R 《Protein science : a publication of the Protein Society》2001,10(5):923-926
A new class of matrix metalloproteinase (MMP) inhibitors has been identified by screening a collection of compounds against stromelysin. The inhibitors, 2,4,6-pyrimidine triones, have proven to be potent inhibitors of gelatinases A and B. An X-ray crystal structure of one representative compound bound to the catalytic domain of stromelysin shows that the compounds bind at the active site and ligand the active-site zinc. The pyrimidine triones mimic substrates in forming hydrogen bonds to key residues in the active site, and provide opportunities for placing appropriately chosen groups into the S1' specificity pocket of MMPS: A number of compounds have been synthesized and assayed against stromelysin, and the variations in potency are explained in terms of the binding mode revealed in the X-ray crystal structure. 相似文献
4.
Blagg JA Noe MC Wolf-Gouveia LA Reiter LA Laird ER Chang SP Danley DE Downs JT Elliott NC Eskra JD Griffiths RJ Hardink JR Haugeto AI Jones CS Liras JL Lopresti-Morrow LL Mitchell PG Pandit J Robinson RP Subramanyam C Vaughn-Bowser ML Yocum SA 《Bioorganic & medicinal chemistry letters》2005,15(7):1807-1810
Through the use of computational modeling, a series of pyrimidinetrione-based inhibitors of MMP-13 was designed based on a lead inhibitor identified through file screening. Incorporation of a biaryl ether moiety at the C-5 position of the pyrimidinetrione ring resulted in a dramatic enhancement of MMP-13 potency. Protein crystallography revealed that this moiety binds in the S(1)(') pocket of the enzyme. Optimization of the C-4 substituent of the terminal aromatic ring led to incorporation of selectivity versus MMP-14 (MT-1 MMP). Structure activity relationships of the biaryl ether substituent are presented as is pharmacokinetic data for a compound that meets our in vitro potency and selectivity goals. 相似文献
5.
Lu IL Lee SJ Tsu H Wu SY Kao KH Chien CH Chang YY Chen YS Cheng JH Chang CN Chen TW Chang SP Chen X Jiaang WT 《Bioorganic & medicinal chemistry letters》2005,15(13):3271-3275
To find potent and selective inhibitors of dipeptidyl peptidase IV (DPP-IV), we synthesized a series of 2-cyanopyrrolidine with P2-site 4-substituted glutamic acid derivatives and tested their activities against DPP-IV, DPP8, and DPP-II. Analogues that incorporated a bulky substituent at the first carbon position of benzylamine or isoquinoline showed over 30-fold selectivity for DPP-IV over both DPP8 and DPP-II. From structure-activity relationship studies, we speculate that the S2 site of DPP8 might be similar to that of DPP-IV, while DPP-IV inhibitor with N-substituted glycine in the P2 site and/or with a moiety involving in hydrophobic interaction with the side chain of Phe357 might provide a better selectivity for DPP-IV over DPP8. 相似文献
6.
R W Sarver P Yuan V P Marshall G L Petzold R A Poorman J DeZwaan B J Stockman 《Biochimica et biophysica acta》1999,1434(2):304-316
Interactions of stromelysin with a series of inhibitors representative of three chemical templates with distinct binding modes were examined. Unfolding temperatures for inhibitor complexes were 10 degrees C to 15 degrees C greater than for apo stromelysin. Minor changes in ellipticity in the far-UV CD spectra of complexes indicated that ligand-induced conformational changes were localized to the binding site and did not involve gross changes in protein folding. Isothermal titrating calorimetry of thiadiazole-containing inhibitors, which bind in the S(1)-S(3) subsites of stromelysin, indicated that the binding interaction was exothermic and only slightly favorable entropically. Near-UV CD spectra showed large positive ellipticity increases from 250 to 300 nm, consistent with an interaction between the benzene ring of the inhibitor and stromelysin residues Tyr155 and Tyr168. Interactions between stromelysin and amide-hydroxamate ligands, which bind in the S(')(1)-S(')(3) subsites, were found to be both enthalpically and entropically driven. Binding of this class of ligands resulted in modest negative ellipticity changes at 260-285 nm and positive increases at 292 nm. Stromelysin complexed to a lactam-hydroxamate inhibitor with structure extending into both the S(1)-S(3) and S(')(1)-S(')(3) subsites showed increased ellipticity at 245 nm and negative changes at 260-285 and 295 nm. 相似文献
7.
A series of 16 1-phenyl-1H-1,2,3-triazoles with substituents at both the 4- and 5-positions of the triazole ring were synthesized, and a total of 49 compounds, including previously reported 4- or 5-monosubstituted analogues, were examined for their ability to inhibit the specific binding of [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB), a non-competitive antagonist, to human homo-oligomeric beta3 and hetero-oligomeric alpha1beta2gamma2 gamma-aminobutyric acid (GABA) receptors. Among all tested compounds, the 4-n-propyl-5-chloromethyl analogue of 1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-1,2,3-triazole showed the highest level of affinity for both beta3 and alpha1beta2gamma2 receptors, with K(i) values of 659pM and 266nM, respectively. Most of the tested compounds showed selectivity for beta3 over alpha1beta2gamma2 receptors. Among all 1-phenyl-1H-1,2,3-triazoles, the 4-n-propyl-5-ethyl analogue exhibited the highest (>1133-fold) selectivity, followed by the 4-n-propyl-5-methyl analogue of 1-(2,6-dibromo-4-trifluoromethylphenyl)-1H-1,2,3-triazole with a >671-fold selectivity. The 2,6-dichloro plus 4-trifluoromethyl substitution pattern on the benzene ring was found to be important for the high affinity for both beta3 and alpha1beta2gamma2 receptors. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) provided similar contour maps, revealing that an electronegative substituent at the 4-position of the benzene ring, a compact, hydrophobic substituent at the 4-position of the triazole ring, and a small, electronegative substituent at the 5-position of the triazole ring play significant roles for the high potency in beta3 receptors. Molecular docking studies suggested that the putative binding sites for 1-phenyl-1H-1,2,3-triazole antagonists are located in the channel-lining 2'-6' region of the second transmembrane segment of beta3 and alpha1beta2gamma2 receptors. A difference in the hydrophobic environment at the 2' position might underlie the selectivity of 1-phenyl-1H-1,2,3-triazoles for beta3 over alpha1beta2gamma2 receptors. The compounds that had high affinity for beta3 receptors with homology to insect GABA receptors showed insecticidal activity against houseflies with LD(50) values in the pmol/fly range. The information obtained in the present study should prove helpful for the discovery of selective insect control chemicals. 相似文献
8.
Matrix metalloproteinases (MMPs) cleave and degrade most components of the extracellular matrix, and unregulated MMP activity has been correlated to cancer and metastasis. Hence there is a burgeoning need to develop inhibitors that bind selectively to structurally similar MMPs. The inhibition profiles of peptidomimetics containing C(α) substituents at the α,β unsaturated carbon were evaluated against the recombinant forms of ADAM17, MMP1, and MMP9. The dicarboxylic acid D2 and hydroxamate C2 inhibited MMP9 but not MMP1. The unsaturated compound E2 displayed selective inhibition for MMP1, compared with the saturated precursor C2, with an IC(50) value of 3.91 μm. The molecular basis for this selectivity was further investigated by the molecular docking of E2 and D2 into the active sites of MMP1 and MMP9. These data demonstrate hydrogen-bonding interactions between the carbonyl group of the C(α) substituent of E2 and the side chain of Asn180 present in the active site of MMP1. Conversely, the docked MMP9-D2 structure shows hydrophobic and hydrogen bonding between the ligand's morpholine substituent and second carboxylic acid group with Leu187 and an amide, respectively. This study suggests that substituents other than P(1)' and P(2)' may confer selectivity among MMPs and may aid in the search for novel lead compounds. 相似文献
9.
Wenqing Yao Michael Chao Zelda R Wasserman Rui Qin Liu Maryanne B Covington Robert Newton David Christ Ruth R Wexler Carl P Decicco 《Bioorganic & medicinal chemistry letters》2002,12(1):101-104
A series of cis-1(S)2(R)-amino-2-indanol based compounds with a biphenylmethyl group at the P1' position was found to be potent aggrecanase inhibitors. Both compounds 2j and 2n possessed very high aggrecanase affinity (IC(50)=1.5nM), and showed excellent selectivity over MMP-1 and MMP-9, with moderate selectivity against MMP-2. 相似文献
10.
Ashok D. Pehere Steven Nguyen Sarah K. Garlick Danny W. Wilson Irene Hudson Matthew J. Sykes James D. Morton Andrew D. Abell 《Bioorganic & medicinal chemistry》2019,27(2):436-441
The 26S proteasome and calpain are linked to a number of important human diseases. Here, we report a series of analogues of the prototypical tripeptide aldehyde inhibitor MG132 that show a unique combination of high activity and selectivity for calpains over proteasome. Tripeptide aldehydes (1–3) with an aromatic P3 substituent show enhanced activity and selectivity against ovine calpain 2 relative to chymotrypsin-like activity of proteasome. Docking studies reveal the key contacts between inhibitors and calpain to confirm the importance of the S3 pocket with respect to selectivity between calpains 1 and 2 and the proteasome. 相似文献
11.
P1 Phenethyl peptide boronic acid inhibitors of HCV NS3 protease 总被引:1,自引:0,他引:1
Priestley ES De Lucca I Ghavimi B Erickson-Viitanen S Decicco CP 《Bioorganic & medicinal chemistry letters》2002,12(21):3199-3202
A series of peptide boronic acids containing extended, hydrophobic P1 residues was prepared to probe the shallow, hydrophobic S1 region of HCV NS3 protease. The p-trifluoromethylphenethyl P1 substituent was identified as optimal with respect to inhibitor potency for NS3 and selectivity against elastase and chymotrypsin. 相似文献
12.
Hopkins CR Czekaj M Kaye SS Gao Z Pribish J Pauls H Liang G Sides K Cramer D Cairns J Luo Y Lim HK Vaz R Rebello S Maignan S Dupuy A Mathieu M Levell J 《Bioorganic & medicinal chemistry letters》2005,15(11):2734-2737
A new series of novel mast cell tryptase inhibitors is reported, which features the use of an indole structure as the hydrophobic substituent on a m-benzylaminepiperidine template. The best members of this series display good in vitro activity and excellent selectivity against other serine proteases. 相似文献
13.
Zvarec O Polyak SW Tieu W Kuan K Dai H Pedersen DS Morona R Zhang L Booker GW Abell AD 《Bioorganic & medicinal chemistry letters》2012,22(8):2720-2722
Herein we outline the antibacterial activity of amino acid containing thiazolidinediones and rhodanines against Gram-positive bacteria Staphylococcus aureus ATCC 31890, Staphylococcus epidermidis and Bacillus subtilis ATCC 6633. The rhodanine derivatives were generally more active than the analogous thiazolidinediones. Compounds of series 5 showed some selectivity for Bacillus subtilis ATCC 6633, the extent of which is enhanced by the inclusion of a non-polar amino acid at the 5-position of the core thiazolidinediones and rhodanines scaffolds. SAR data of series 8 demonstrated improved activity against the clinically more significant Staphylococci with selectivity over Bacillus subtilis ATCC 6633 induced by introduction of a bulky aryl substituent at the 5-position of the core scaffolds. 相似文献
14.
Ananthan S Khare NK Saini SK Davis P Dersch CM Porreca F Rothman RB 《Bioorganic & medicinal chemistry》2003,11(18):4143-4154
A series of pyridomorphinans possessing an aryl (10a-s) or heteroaryl (11a-h) substituent at the 5'-position of the pyridine ring of 17-cyclopropylmethyl-4,5 alpha-epoxypyrido[2',3':6,7]morphinan was synthesized and evaluated for binding and functional activity at the opioid delta, mu, and kappa receptors. All of these pyridomorphinans bound with higher affinity at the delta site than at mu or kappa sites. The binding data on isomeric compounds revealed that there exists greater bulk tolerance for substituents placed at the o-position of the phenyl ring than at m- or p-positions. Among the ligands examined, the 2-chlorophenyl (10l), 2-nitrophenyl (10n), 2-pyridyl (11a), and 4-quinolinyl (11g) compounds bound to the delta receptor with subnanomolar affinity. Compound 10c with the p-tolyl substituent displayed the highest mu/delta selectivity (ratio=42) whereas compound 10l with the 2-chlorophenyl substituent displayed the highest kappa/delta selectivity (ratio=23). At 10 microM concentration, the in vitro functional activity determined using [(35)S]GTP-gamma-S binding assays showed that all of the compounds were antagonists devoid of any significant agonist activity at the delta, mu, and kappa receptors. Antagonist potency determinations of three selected ligands revealed that the p-tolyl compound 10c is a potent delta selective antagonist. In the [(35)S]GTP-gamma-S assays this compound had a functional antagonist K(i) value of 0.2, 4.52, and 7.62 nM at the delta, mu, and kappa receptors, respectively. In the smooth muscle assays 10c displayed delta antagonist potency with a K(e) value of 0.88 nM. As an antagonist, it was 70-fold more potent at the delta receptors in the MVD than at the mu receptors in the GPI. The in vitro delta antagonist profile of this pyridomorphinan 10c resembles that of the widely used delta selective antagonist ligand naltrindole. 相似文献
15.
Jarvis TC Bouhana KS Lesch ME Brown SA Parry TJ Schrier DJ Hunt SW Pavco PA Flory CM 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(1):493-498
In this paper we describe a method for validating therapeutic gene targets in arthritic disease. Ribozymes are catalytic oligonucleotides capable of highly sequence-specific cleavage of RNA. We designed ribozymes that cleave the mRNA encoding stromelysin, a matrix metalloproteinase implicated in cartilage catabolism. Ribozymes were initially screened in cultured fibroblasts to identify sites in the mRNA that were accessible for binding and cleavage. Accessible sites for ribozyme binding were found in various regions of the mRNA, including the 5' untranslated region, the coding region, and the 3' untranslated region. Several ribozymes that mediated sequence-specific and dose-dependent inhibition of stromelysin expression were characterized. Site selection in cell culture was predictive of in vivo bioactivity. An assay for measuring cartilage catabolism in rabbit articular cartilage explants was developed. Ribozymes inhibited IL-1-stimulated stromelysin mRNA expression in articular cartilage explants, yet failed to inhibit proteoglycan degradation. This indicated that up-regulation of stromelysin was not essential for IL-1-induced cartilage catabolism. Broad applications of this approach in therapeutic target validation are discussed. 相似文献
16.
Structure-activity relationships are described for a series of succinyl hydroxamic acids 1a-o and their carboxylic acid analogues 2a-o as inhibitors of matrix metalloproteases MMP-3 and MMP-2. For this series (P1' = (CH2)3Ph, P2' = t-Bu) selectivity for the inhibition of MMP-2 was found to be strongly dependent on P3'. 相似文献
17.
Huang A Joseph-McCarthy D Lovering F Sun L Wang W Xu W Zhu Y Cui J Zhang Y Levin JI 《Bioorganic & medicinal chemistry》2007,15(18):6170-6181
A series of beta-sulfonyl hydroxamate TACE inhibitors, bearing a butynylamino or a butynyloxy P1' group, was designed and synthesized. Of the compounds investigated, 22 has excellent potency against isolated TACE enzyme, shows good selectivity over MMP-2 and MMP-13, and oral activity in an in vivo mouse model of TNF-alpha production. 相似文献
18.
John I. Trujillo James R. Kiefer Wei Huang Atli Thorarensen Li Xing Nicole L. Caspers Jacqueline E. Day Karl J. Mathis Kuniko K. Kretzmer Beverley A. Reitz Robin A. Weinberg Roderick A. Stegeman Ann Wrightstone Lori Christine Robert Compton Xiong Li 《Bioorganic & medicinal chemistry letters》2009,19(3):908-911
The inhibition of PKC-ζ has been proposed to be a potential drug target for immune and inflammatory diseases. A series of 2-(6-phenyl-1H indazol-3-yl)-1H-benzo[d]imidazoles with initial high crossover to CDK-2 has been optimized to afford potent and selective inhibitors of protein kinase c-zeta (PKC-ζ). The determination of the crystal structures of key inhibitor:CDK-2 complexes informed the design and analysis of the series. The most selective and potent analog was identified by variation of the aryl substituent at the 6-position of the indazole template to give a 4-NH2 derivative. The analog displays good selectivity over other PKC isoforms (α, βII, γ, δ, ε, μ, θ, η and ι/λ) and CDK-2, however it displays marginal selectivity against a panel of other kinases (37 profiled). 相似文献
19.
Zhang X Gonnella NC Koehn J Pathak N Ganu V Melton R Parker D Hu SI Nam KY 《Journal of molecular biology》2000,301(2):513-524
The full three-dimensional structure of the catalytic domain of human collagenase-3 (MMP-13) complexed to a potent, sulfonamide hydroxamic acid inhibitor (CGS 27023) has been determined by NMR spectroscopy. The results reveal a core domain for the protein consisting of three alpha-helices and five beta-sheet strands with an overall tertiary fold similar to the catalytic domains of other matrix metalloproteinase family members. The S1' pocket, which is the major site of hydrophobic binding interaction, was found to be a wide cleft spanning the length of the protein and presenting facile opportunity for inhibitor extension deep into the pocket. Comparison with the reported X-ray structure of collagenase-3 showed evidence of flexibility for the loop region flanking the S1' pocket in both NMR and X-ray data. This flexibility was corroborated by NMR dynamics studies. Inhibitor binding placed the methoxy phenyl ring in the S1' pocket with the remainder of the molecule primarily solvent-exposed. The binding mode for this inhibitor was found to be similar with respect to stromelysin-1 and collagenase-1; however, subtle comparative differences in the interactions between inhibitor and enzyme were observed for the three MMPs that were consistent with their respective binding potencies. 相似文献
20.
J P Case R Lafyatis G K Kumkumian E F Remmers R L Wilder 《Journal of immunology (Baltimore, Md. : 1950)》1990,145(11):3755-3761