Drug design and discovery最新文献_第5页

Pharmacophore/receptor models for GABA(A)/BzR alpha2beta3gamma2, alpha3beta3gamma2 and alpha4beta3gamma2 recombinant subtypes. Included volume analysis and comparison to alpha1beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2 subtypes. GABA(A)/BzR alpha2beta3gamma2、alpha3beta3gamma2和alpha4beta3gamma2重组亚型药效团/受体模型。包括对alpha1beta3gamma2、alpha5beta3gamma2和alpha6beta3gamma2亚型的体积分析和比较。

Drug design and discovery Pub Date : 2000-01-01

X He, Q Huang, C Ma, S Yu, R McKernan, J M Cook

{"title":"Pharmacophore/receptor models for GABA(A)/BzR alpha2beta3gamma2, alpha3beta3gamma2 and alpha4beta3gamma2 recombinant subtypes. Included volume analysis and comparison to alpha1beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2 subtypes.","authors":"X He, Q Huang, C Ma, S Yu, R McKernan, J M Cook","doi":"","DOIUrl":"","url":null,"abstract":"Pharmacophore/receptor models for 6 recombinant GABA(A)/BzR subtypes (alphax beta3gamma2, x = 1-6) have been established via an SAR ligand mapping approach. This study was based on the affinities of 166 BzR ligands at 6 distinct (alpha1-6beta3gamma2) recombinant GABA(A)/BzR receptor subtypes from at least twelve different structural families. Examination of the included volumes indicated that the shapes of binding pockets for alpha1, alpha2 and alpha3 subtypes are very similar to each other. Region L2 for the alpha5 containing subtype appeared to be larger in size than the analogous region of the other receptor subtypes. Region L(Di), in contrast, appeared to be larger in the alpha1 subtype than in the other subtypes. Moreover, region L3 in the alpha6 subtype is either very small or nonexistent in this diazepam insensitive \"DI\" subtype as compared to the other subtypes. Preliminary results for the alpha4-containing receptor subtype (DI) indicate that L3 in the alpha4 subtype suffers a similar fate. Use of the pharmacophore/receptor models for these subtypes have resulted in the design of novel BzR ligands selective for the alpha5beta3gamma2, receptor subtype.","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"17 2","pages":"131-71"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21875794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Substituted 3-phenylsulfonylquinazoline-2,4-dione derivatives as novel nonpeptide inhibitors of human heart chymase. 取代3-苯基磺酰基喹唑啉-2,4-二酮衍生物作为新型人心脏酶的非肽抑制剂。

Drug design and discovery Pub Date : 2000-01-01

H Fukami, S Imajo, A Ito, S Kakutani, H Shibata, M Sumida, T Tanaka, S Niwata, M Saitoh, Y Kiso, M Miyazaki, H Okunishi, H Urata, K Arakawa

{"title":"Substituted 3-phenylsulfonylquinazoline-2,4-dione derivatives as novel nonpeptide inhibitors of human heart chymase.","authors":"H Fukami, S Imajo, A Ito, S Kakutani, H Shibata, M Sumida, T Tanaka, S Niwata, M Saitoh, Y Kiso, M Miyazaki, H Okunishi, H Urata, K Arakawa","doi":"","DOIUrl":"","url":null,"abstract":"A series of 3-phenylsulfonylquinazoline-2,4-dione derivatives have been synthesized and evaluated for their ability to inhibit human heart chymase. The structure-activity relationship studies on these compounds gave the following results. The phenyl moiety of quinazoline participates in a hydrophobic interaction where an optimum size is required. In this moiety, 7-chloroquinazoline is the best moiety for inhibiting chymase, chymotrypsin and cathepsin G. A 3-phenylsulfonyl moiety substituted with hydrophobic electron-withdrawing groups at the 4-position potentiated the activity. Anthranil moiety also enhanced the activity. Pyridylmethyl and N-pyridylacetamide at the 1-position gave an IC50 in the order of 10(-8)M. Molecular modeling studies on the interaction of 7-chloro-3-(4-chlorophenylsulfonyl) quinazoline-2,4(1H, 3H)-dione (4) with the active site of human heart chymase suggested that the phenyl moiety of quinazoline interacts with the hydrophobic P1 pocket, the 3-phenylsulfonyl moiety resides in the S1'-S2' subsites, the moiety at the 1-position locates in the S2-S3 subsites and the 4-carbonyl and 3-sulfonyl group interact with the oxyanion hole and the His57 side-chain of chymase, respectively.","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"17 1","pages":"69-84"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21767125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neuronal N-type calcium channel blockers: a series of 4-piperidinylaniline analogs with analgesic activity. 神经元n型钙通道阻滞剂:一系列具有镇痛活性的4-哌啶苯胺类似物。

Drug design and discovery Pub Date : 2000-01-01

L Y Hu, T R Ryder, M F Rafferty, K M Siebers, T Malone, A Chatterjee, M R Feng, S M Lotarski, D M Rock, S J Stoehr, C P Taylor, M L Weber, G P Miljanich, E Millerman, B G Szoke

引用次数: 0

Conformational landscape of selective mu-opioid agonists in gas phase and in aqueous solution: the fentanyl series. 选择性阿片激动剂在气相和水溶液中的构象景观:芬太尼系列。

Drug design and discovery Pub Date : 2000-01-01

G Subramanian, D M Ferguson

引用次数: 0

QSAR and CoMFA: a perspective on the practical application to drug discovery. QSAR和CoMFA:在药物发现中的实际应用。

Drug design and discovery Pub Date : 2000-01-01

B L Podlogar, D M Ferguson

引用次数: 0

Structure-activity relationship at the leucine side chain in a series of N,N-dialkyldipeptidyl-amines as N-type calcium channel blockers. N,N-二烷基二肽基胺作为N型钙通道阻滞剂系列中亮氨酸侧链的构效关系

Drug design and discovery Pub Date : 2000-01-01

T R Ryder, L Y Hu, M F Rafferty, S M Lotarski, D M Rock, S J Stoehr, C P Taylor, M L Weber, G P Miljanich, E Millerman, B G Szoke

引用次数: 0

Synthesis and evaluation of 4-(N,N-diarylamino)piperidines with high selectivity to the delta-opioid receptor: a combined 3D-QSAR and ligand docking study. 对阿片受体具有高选择性的4-(N,N-二芳胺)哌啶的合成与评价:3D-QSAR与配体对接的联合研究。

Drug design and discovery Pub Date : 2000-01-01

B L Podlogar, G I Poda, D A Demeter, S P Zhang, J R Carson, L A Neilson, A B Reitz, D M Ferguson

{"title":"Synthesis and evaluation of 4-(N,N-diarylamino)piperidines with high selectivity to the delta-opioid receptor: a combined 3D-QSAR and ligand docking study.","authors":"B L Podlogar, G I Poda, D A Demeter, S P Zhang, J R Carson, L A Neilson, A B Reitz, D M Ferguson","doi":"","DOIUrl":"","url":null,"abstract":"A series of 4-(N,N-diarylamino)piperidines are synthesized and evaluated for high affinity binding and selectivity to the delta-opioid receptor using a combination of 3D-QSAR and molecular docking techniques. Based on experimental ligand binding data to both mu- and delta- opioid receptors, CoMFA fields are generated and applied to identify potential ligand modifications to further optimize lead compounds. Molecular docking experiments to the delta-receptor are also reported that explain the CoMFA trends predicted as well as the differential binding and selectivity displayed by various compounds in the series. An analysis of the binding site model proposed indicates the piperidines take advantage of 3 key sites or binding domains within the delta-receptor. These include an aromatic pocket (approximately 1/3 into the receptor cavity), an aspartic acid residue (which serves as a docking point for the piperidinyl cationic amine) and a hydrophobic pocket at the extracellular boundary of the receptor cavity. Links are established between ligand modification and amino acid composition at these sites in mu and delta, providing new insight to the structural basis to binding and selectivity across the series and for related piperazines (i.e. SNC80 and BW373U86). Results are also presented that indicate delta- and mu-selectivity may be determined at alternate sites, suggesting opioid receptors may display multiple binding domains. The model is further supported by comparisons with opiate binding modes and site directed mutagenesis studies and is finally applied to suggest new strategies in ligand design.","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"17 1","pages":"34-50"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21768464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Driving drug discovery and patient therapy via the encapsulation and fusion of knowledge. 通过知识的封装和融合推动药物发现和患者治疗。

Drug design and discovery Pub Date : 1999-11-01

M A Collins, I Shaw, D C Billington

引用次数: 0

Inhibition of beta 2glycoprotein I binding to anionic phospholipids: a strategy for the development of antiphospholipid syndrome-specific drugs. 抑制β 2糖蛋白I与阴离子磷脂的结合:开发抗磷脂综合征特异性药物的策略

Drug design and discovery Pub Date : 1999-11-01

J D Kohles, M Petersheim, V A DeBari

{"title":"Inhibition of beta 2glycoprotein I binding to anionic phospholipids: a strategy for the development of antiphospholipid syndrome-specific drugs.","authors":"J D Kohles, M Petersheim, V A DeBari","doi":"","DOIUrl":"","url":null,"abstract":"The binding of beta 2glycoprotein I (beta 2GPI) to anionic phospholipids (PL) leads to the presentation of one or more epitopes recognized by autoantibodies from patients with antiphospholipid syndrome (APS). The inhibition of beta 2GPI binding to PL mixtures coated on polystyrene microtiter wells (MTW) and to large, multilamellar PL vesicles (LMV) was examined. Inhibitors included phosphorylated monosaccharide metabolites, myo-inositol monophosphate (IMP), hexaphosphate (IHP) and hexasulfate (IHS), pyrophosphate (PPi), methyl bisphosphonate (MBP) and phenyl phosphonate, and a series of carboxylic and aromatic sulfonic acids. Inhibitors were incubated with beta 2GPI at 37 degrees C for 2 hr either with dimyristoylphosphatidic acid, 80%/dimyristoylphosphatidyl choline, 20% (DMPA/DMPC) coated on MTW or in a suspension of LMV. Phospholipid-bound beta 2GPI to PA/PC on MTW was detected using an immunoassay based on rabbit anti-beta 2GPI; free beta 2GPI (not bound to LMV) was detected by fluorescence spectroscopy. Inhibition was studied over the range 0.01-9.0 mumoles/10(-4)L (0.1-90 mM). Inhibition at maximum concentration in the MTW system ranged from 0.1% (for ADP) to > 94% (for IHP). IHP also provided the greatest inhibition in the LMV system (76%) and was also effective in displacing beta 2GPI already bound to PL surfaces (approximately 50% displaced at 0.25 mM). These data suggest that a strategy for development of therapeutic agents for APS may be based on the use of small cyclic, organic oligoanions such as inositol derivatives to act as ligands for lysine residues at the PL binding site of beta 2GPI.","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"16 3","pages":"227-36"},"PeriodicalIF":0.0,"publicationDate":"1999-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21480745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis of combinatorial libraries of 3,4,5-trisubstituted 2(5H)-furanones. Part One: Construction of a sub-library of halogenated 5-alkoxy-2(5H)-furanones. 3,4,5-三取代2(5H)-呋喃酮组合文库的合成。第一部分:卤代5-烷氧基-2(5H)-呋喃酮子库的构建。

Drug design and discovery Pub Date : 1999-11-01

E Lattmann, D C Billington, C A Langley

引用次数: 0