Drug design and discovery最新文献_第8页

Evaluation of drug disappearance from nasal cavity by the deposit method. 用沉淀法评价鼻腔药物消失。

Drug design and discovery Pub Date : 1998-10-01

K Aikawa, H Uda, S Tanaka, H Shimamura, S Tsuchiya

引用次数: 0

Synthesis and antimycobacterial activity of some heteroarylcarboxamidrazone derivatives. 一些杂芳基羧氨基腙衍生物的合成及其抑菌活性。

Drug design and discovery Pub Date : 1998-10-01

D C Billington, M D Coleman, J Ibiabuo, P A Lambert, D L Rathbone, K J Tims

引用次数: 0

Rational design of inhibitors for drug-resistant HIV-1 aspartic protease mutants. 耐药HIV-1天冬氨酸蛋白酶突变体抑制剂的合理设计。

Drug design and discovery Pub Date : 1998-10-01

V Frecer, S Miertus, A Tossi, D Romeo

{"title":"Rational design of inhibitors for drug-resistant HIV-1 aspartic protease mutants.","authors":"V Frecer, S Miertus, A Tossi, D Romeo","doi":"","DOIUrl":"","url":null,"abstract":"This report describes a method for the assessment of inhibitor binding affinities to wild type HIV-1 aspartic protease and to its drug-resistant mutant forms. We have elaborated a refined method for molecular modeling of the 3D structures of mutant enzymes and enzyme-inhibitor complexes based on the crystal structure of the wild type form, which employs a full thermodynamic cycle. Model complexes of four HIV-1 aspartic protease mutants with ten analogs of the A77003 inhibitor were considered. Predictions of inhibition efficiency, resistance potential, and hydrophilicity of the redesigned A77003 analogs were obtained by employing molecular mechanics for the evaluation of enzyme-inhibitor complexation energy and the polarizable continuum model for the estimation of solvent effects. Simple qualitative indicators for structural modifications aimed at overcoming the emergence of HIV resistance to protease inhibitors and at increasing the bioavailability of pseudopeptide inhibitors are examined. A semi-quantitative method for the description of enzyme-ligand binding and its implications for the rational design of inhibitors with higher binding affinity towards emerging HIV PR mutants is presented.","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"15 4","pages":"211-31"},"PeriodicalIF":0.0,"publicationDate":"1998-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21406420","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 and preliminary in vitro cytotoxic activity of novel cisplatin and carboplatin analogues. 新型顺铂和卡铂类似物的合成及其体外细胞毒活性的初步研究。

Drug design and discovery Pub Date : 1998-10-01

A Séné, G Bérubé, R C Gaudreault

引用次数: 0

Correspondence analysis of protein kinase C (PKC) inhibition by bis-basic substituted benzamides. 双碱取代苯酰胺抑制蛋白激酶C (PKC)的对应分析。

Drug design and discovery Pub Date : 1998-10-01

J Gilbert, M Cheminant, E Bignon, M Pons, T Ojasoo, J C Doré

{"title":"Correspondence analysis of protein kinase C (PKC) inhibition by bis-basic substituted benzamides.","authors":"J Gilbert, M Cheminant, E Bignon, M Pons, T Ojasoo, J C Doré","doi":"","DOIUrl":"","url":null,"abstract":"We describe the synthesis of a novel series of bis-basic substituted benzamides and their relative potency in inhibiting rat brain protein kinase alpha (PKC alpha) activity. None of the compounds inhibited enzyme activity via the catalytic domain but several did via the regulatory domain at 1-5 microM concentrations. Inhibition was comparable to that of several di- and triphenylacrylonitriles and triphenylethylenes. According to a multivariate factor (correspondence) analysis of QSAR descriptors, hydrophobicity (log p) and hydration energy were the most discriminant descriptors, much more so than molecular mass, molar refractivity, polarizability, molecular volume and solvent-accessible surface. Inhibitory activity was correlated with high hydrophobicity and low hydration energy. The higher potency of GL9 (N,N'-oxalyl-bis[(o-amino)[2-(diethylamino)ethyl]-benzamide]) that differed from its congener (GL25) by the presence of an oxamide rather than succinamide moiety was tentatively explained by the greater negative charges associated with the carbonyl groups of its oxamide residue. The higher potency of GL22 (N,N'-tere-phthalyl-bis[(o-amino)[2-(diethylamino)ethyl]-benzamide ] in which an aromatic ring is inserted between two benzamide moieties in para, para' rather than ortho, ortho' positions as in GL23 might be due to a planar conformation facilitating membrane insertion. In conclusion, correspondence analysis is a neat way of highlighting similarities and differences in molecular properties (QSAR descriptors and potency). Therapeutic doses of many classes of drug might interfere with the regulatory domain of PKC alpha if, like our test-compounds, they have basic side-chain(s), high hydrophobicity, low hydration energy, a planar conformation and/or a highly charged reactive (oxamide) moiety.","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"15 4","pages":"253-67"},"PeriodicalIF":0.0,"publicationDate":"1998-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21406423","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

C16 and C17 derivatives of estradiol as inhibitors of 17 beta-hydroxysteroid dehydrogenase type 1: chemical synthesis and structure-activity relationships. 雌二醇的C16和C17衍生物作为17 β -羟基类固醇脱氢酶1型抑制剂:化学合成和构效关系

Drug design and discovery Pub Date : 1998-05-01

K M Sam, R P Boivin, M R Tremblay, S Auger, D Poirier

{"title":"C16 and C17 derivatives of estradiol as inhibitors of 17 beta-hydroxysteroid dehydrogenase type 1: chemical synthesis and structure-activity relationships.","authors":"K M Sam, R P Boivin, M R Tremblay, S Auger, D Poirier","doi":"","DOIUrl":"","url":null,"abstract":"As a first part of our research focused on the synthesis of 17 beta-HSD type 1 inhibitors without estrogenic activity, we needed to identify a small, easy-to-handle pharmacophore able to block the enzymatic activity. Previous studies on the active site of the enzyme by affinity labeling gave us a basis for the design of steroidal inhibitors derivatives. Several estradiol derivatives bearing a short (three carbons) side chain in position 17 alpha or 16 alpha were synthesized and tested for their ability to inhibit the transformation of estrone into estradiol by 17 beta-HSD type 1 (cytosolic fraction of human placenta). We found that 16 alpha-derivatives of estradiol gave better 17 beta-HSD inhibition than their corresponding 17 alpha analogs. Among several chemical groups used in this study, we conclude that better 17 beta-HSD inhibition was obtained for compounds with a good leaving group at the end of side chain. Thus, an iodopropyl or a bromopropyl side chain at C16 alpha of estradiol (E2) inhibit efficiently the 17 beta-HSD type 1 with IC50 values of 0.42 and 0.46 microM, respectively. Their 17-keto analogs inhibit also the enzyme activity similarly. Since this kind of compounds inhibit the 17 beta-HSD type 1 in time-dependent manner and that enzymatic activity cannot be restored later, we conclude to inhibitor of inactivator type. This conclusion is in accordance with the correlation observed between the ability of leaving group to dissociate and their potency to inhibit 17 beta-HSD type 1. We have also observed that additional addition of untritiated estrone protect the enzyme against the inactivation caused by 16 alpha-bromopropyl-E2 suggesting a competitive inhibitor of 17 beta-HSD. The bromopropyl pharmacophore was then selected to be further added onto an antiestrogenic steroid nucleus.","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"15 3","pages":"157-80"},"PeriodicalIF":0.0,"publicationDate":"1998-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20606450","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

Design and synthesis of small molecule interleukin-1 receptor antagonists based on a benzene template. 基于苯模板的小分子白介素-1受体拮抗剂的设计与合成。

Drug design and discovery Pub Date : 1998-05-01

R Sarabu, J P Cooper, C M Cook, P Gillespie, A V Perrotta, G L Olson

引用次数: 0

Design and discovery of RWJ 22108--a novel bronchoselective calcium channel blocker. 新型支气管选择性钙通道阻滞剂rwj22108的设计与发现。

Drug design and discovery Pub Date : 1998-05-01

J H Dodd, C F Schwender, J B Moore, D M Ritchie, Y Gray-Nunez, D Loughney, T Kirchner, W C Miller, S Mockoviak

引用次数: 0

Docking analysis of a series of cytochrome P-450(14) alpha DM inhibiting azole antifungals. 一系列细胞色素P-450(14) α DM抑制唑类抗真菌药物的对接分析。

Drug design and discovery Pub Date : 1998-05-01

T T Talele, V Hariprasad, V M Kulkarni