Drug design and discovery最新文献

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QSAR with electrotopological state atom index: human factor Xa inhibitor N2-aroylanthranilamides. 具有电拓扑状态原子指数的QSAR:人因子Xa抑制剂n2 -芳酰氰胺。
Drug design and discovery Pub Date : 2002-01-01
Kunal Roy, A U De, Chandana Sengupta
{"title":"QSAR with electrotopological state atom index: human factor Xa inhibitor N2-aroylanthranilamides.","authors":"Kunal Roy,&nbsp;A U De,&nbsp;Chandana Sengupta","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Recently, N2-aroylanthranilamides have been reported as novel series of possible anticoagulant drug candidates and the two aryl rings (A and B) have been suggested to interact with S1 and S4 regions, respectively, of human factor Xa (hfXa). In the present effort, quantitative structure-activity relationship (QSAR) of the hfXa binding affinity of 32 N2-aroylanthranilamides have been attempted, in continuation of our previous report on the QSAR analysis of the data set using linear free energy related (LFER) model, with electrotopological state atom (ETSA) index (Kier and Hall, 1991, Adv. Drug Design., 22, 1-38), to explore the atoms/regions of the compounds that modulate the activity comparatively to the greater extent. The univariate and bivariate relations involving the ETSA values of different common atoms of the compounds show importance of the atom nos. 12, 3 and 17 (arbitrary numbering): B ring carbon bearing meta R2 substituents, C ring carbon bearing R4 substituent, and carbonyl oxygen of A ring amide linkage. The importance of atom 12 is suggested to be due to detrimental effects of meta R2 substituents (B ring) on the hfXa binding affinity, which may be owing to interference in the attainment of the proper orientation of the phenyl ring in the S4 site. Atom 3 signifies the impact of R4 substituents (central C ring) on the binding affinity. Again, atom 17 (carbonyl oxygen of A ring amide linkage) has been suggested to form hydrogen bonding with the NH group of the other amide linkage, producing a pseudo ring and thus stabilizing the structure. The relations were improved further using indicator and physicochemical variables and the present results are in good agreement with the previous findings of the Hansch analysis.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"18 1","pages":"33-43"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22061137","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 5-HT3 receptor affinity of new quinolinecarboxylic acid derivatives. 新型喹啉羧酸衍生物的合成及其5-HT3受体亲和力。
Drug design and discovery Pub Date : 2000-01-01
A Orjales, L Alonso-Cires, P L López-Tudanca, I Tapia, L Labeaga, R Mosquera
{"title":"Synthesis and 5-HT3 receptor affinity of new quinolinecarboxylic acid derivatives.","authors":"A Orjales,&nbsp;L Alonso-Cires,&nbsp;P L López-Tudanca,&nbsp;I Tapia,&nbsp;L Labeaga,&nbsp;R Mosquera","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>A series of quinolinecarboxylic acid amides and an ester with a quinuclidine moiety were synthesized and their in vitro affinities at 5-HT3, 5-HT4, and D2 receptors evaluated by radioligand binding assays. Highest affinity at 5-HT3 receptor corresponded to derivative 5 with Ki = 9.9 nM and with selectivity over 5-HT4 and D2 receptors. Compounds displayed moderate 5-HT3 antagonist activity (ED50 = 10.5-21.5 microg/kg i.v.). The obtained data suggest that the 5-HT3 receptor sites can accommodate the acyl group of the 2-quinoline derivatives. The results indicate the existence of an optimal distance between the lone electron pair of the quinoline nitrogen atom and the azabicyclic nitrogen atom, and a no-pharmacophoric pocket in the 5-HT3 receptor which would hold the fragment at the position 4 of the quinoline ring.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"16 4","pages":"271-9"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21654190","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
New antiherpetic 1,3-phenylene derivatives, inhibitors of the interaction of the HSV-1 origin binding protein (OBP) with DNA. 新的抗疱疹的1,3-苯基衍生物,抑制HSV-1起源结合蛋白(OBP)与DNA的相互作用。
Drug design and discovery Pub Date : 2000-01-01
M Font, C Sanmartín, M L Alonso, L Gracia, M J Losa, B Marquiegui, I Merino, E Nadal, I Ruiz, A Monge, M T Bengoechea, F Cabodevilla, S Elena, J J Martinez-Irujo, L Odriozola, I Peñuelas, E Santiago, F Homa, M W Wathen
{"title":"New antiherpetic 1,3-phenylene derivatives, inhibitors of the interaction of the HSV-1 origin binding protein (OBP) with DNA.","authors":"M Font,&nbsp;C Sanmartín,&nbsp;M L Alonso,&nbsp;L Gracia,&nbsp;M J Losa,&nbsp;B Marquiegui,&nbsp;I Merino,&nbsp;E Nadal,&nbsp;I Ruiz,&nbsp;A Monge,&nbsp;M T Bengoechea,&nbsp;F Cabodevilla,&nbsp;S Elena,&nbsp;J J Martinez-Irujo,&nbsp;L Odriozola,&nbsp;I Peñuelas,&nbsp;E Santiago,&nbsp;F Homa,&nbsp;M W Wathen","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The synthesis of new 1,3-phenylene derivatives and their preliminary evaluation as antivirals (Herpes simplex 1, HSV-1) whose antiherpetic activity can be related with the inhibition of the interaction of the origin binding protein (OBP) with the DNA are presented. The new compounds are adjusted to a previously defined common structural model, consisting of a central aromatic system, which presents two side chains of different lengths in relative position 1, 3; these chains are made up of atomic groups characterized by the alternation of positive and negative centers, situating differently substituted rings, preferably aromatic, at the ends of both chains. Some of these derivatives, such as N,N''-(4-methoxy-1,3-phenylene)bis[N'-(4-nitrophenyl)urea] (2c) or (1,3-phenylene)bis[N-(p-tolyl)aminosulfonyl] (11b), show antiherpetic activity related to the proposed mechanism.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"16 4","pages":"295-315"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21654192","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
Conformational analysis of 2-[2-(3-methoxyphenyl) ethyl]phenoxyalkylamines with high 5-HT2 receptor binding affinity. 具有高5-HT2受体结合亲和力的2-[2-(3-甲氧基苯基)乙基]苯氧烷基胺的构象分析。
Drug design and discovery Pub Date : 2000-01-01
A Kasuya, Y Iwata, N Tanaka, T Ogawa, S Miyamoto
{"title":"Conformational analysis of 2-[2-(3-methoxyphenyl) ethyl]phenoxyalkylamines with high 5-HT2 receptor binding affinity.","authors":"A Kasuya,&nbsp;Y Iwata,&nbsp;N Tanaka,&nbsp;T Ogawa,&nbsp;S Miyamoto","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>A conformational analysis of three groups of 2-[2-(3-methoxyphenyl)ethyl]phenoxyalkylamines with high 5-HT2 receptor binding affinity has been performed using the systematic search. Two groups of compounds with different lengths of alkyl chains connecting the amine nitrogen and the central oxygen showed a one order difference in their 5-HT2 receptor binding affinity. The computational analysis of these compounds confirmed the differences in the N--O distances between the two groups, quantitatively. A probable active conformation was proposed based on a superimposition of the stable conformations over a rigid molecule, mianserin. Two hydroxy derivatives in the third group showed a significant difference in their binding affinity depending on the stereochemistry of the hydroxy group. The difference in the energetically favorable order of the stable conformations reasonably explained the relationship between the stereochemistry and the binding activity. A molecular dynamics-based conformational search was also carried out to compare it with the systematic search.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"17 2","pages":"119-29"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21875793","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 binding studies on a new series of arylpiperazino benzazol-2-one and benzoxazin-3-one derivatives as selective D4 ligands. 一系列新的芳基哌嗪基苯并唑-2- 1和苯并恶嗪-3- 1衍生物选择性D4配体的合成与结合研究。
Drug design and discovery Pub Date : 2000-01-01
P Carato, P Depreux, D Lesieur, M Millan, A Newman-Tancredi, M C Rettori, D H Caignard
{"title":"Synthesis and binding studies on a new series of arylpiperazino benzazol-2-one and benzoxazin-3-one derivatives as selective D4 ligands.","authors":"P Carato,&nbsp;P Depreux,&nbsp;D Lesieur,&nbsp;M Millan,&nbsp;A Newman-Tancredi,&nbsp;M C Rettori,&nbsp;D H Caignard","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>A series of new arylpiperazinomethyl derivatives was designed and studied as potential D4 ligands. The synthesis of these compounds required an original synthetic route. Some of the tested compounds were found to be as potent as clozapine at D4 receptors. Moreover, compounds which displayed a high D2/D4 selectivity ratio (>122) were selected for further pharmacological evaluation.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"17 2","pages":"173-81"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21875795","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
Orphan G-protein coupled receptors: novel drug targets for the pharmaceutical industry. 孤儿g蛋白偶联受体:制药工业的新药物靶点。
Drug design and discovery Pub Date : 2000-01-01
S Wilson, D Bergsma
{"title":"Orphan G-protein coupled receptors: novel drug targets for the pharmaceutical industry.","authors":"S Wilson,&nbsp;D Bergsma","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"17 2","pages":"105-14"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21875792","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
Development of a novel class of monocyclic and bicyclic alkyl amides that exhibit CB1 and CB2 cannabinoid receptor affinity and receptor activation. 一类具有CB1和CB2大麻素受体亲和力和受体激活的新型单环和双环烷基酰胺的开发。
Drug design and discovery Pub Date : 2000-01-01
B A Berglund, P R Fleming, K C Rice, J Y Shim, W J Welsh, A C Howlett
{"title":"Development of a novel class of monocyclic and bicyclic alkyl amides that exhibit CB1 and CB2 cannabinoid receptor affinity and receptor activation.","authors":"B A Berglund,&nbsp;P R Fleming,&nbsp;K C Rice,&nbsp;J Y Shim,&nbsp;W J Welsh,&nbsp;A C Howlett","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>CB1 and CB2 cannabinoid receptors can be activated by several different classes of agonists, including cannabinoids such as delta9-tetrahydrocannabinol and 9-nor-9beta-hydroxyhexahydrocannabinol, and eicosanoids such as arachidonylethanolamide. Structure-activity relationship studies have identified potential pharmacophoric elements for binding to cannabinoid receptors by both cannabinoids and eicosanoids. Molecular models have hypothesized conformational, spatial, and pharmacophoric distance requirements based upon radioligand binding data whereby overlap of pharmacophoric elements of the two classes disclose a low energy conformation of arachidonylethanolamide that can occupy the same receptor space as cannabinoid ligands. To test this model, we have developed a novel class of monocyclic and bicyclic alkyl amide cannabinoid receptor ligands. Further, we predicted a spatial conformation for these compounds in a molecular model based on the pharmacophoric and structural requirements for binding to the CB1 cannabinoid receptor.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"16 4","pages":"281-94"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21654191","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
Applications of biomolecular NMR to drug discovery. 生物分子核磁共振在药物发现中的应用。
Drug design and discovery Pub Date : 2000-01-01
D C Fry, S D Emerson
{"title":"Applications of biomolecular NMR to drug discovery.","authors":"D C Fry,&nbsp;S D Emerson","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"17 1","pages":"13-33"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21768463","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
Hansch analysis of antimalarial cyclic peroxy ketals with physicochemical and electrotopological parameters. 抗疟药环过氧酮的理化和电拓扑参数的Hansch分析。
Drug design and discovery Pub Date : 2000-01-01
K Roy, D K Pal, C Sengupta
{"title":"Hansch analysis of antimalarial cyclic peroxy ketals with physicochemical and electrotopological parameters.","authors":"K Roy,&nbsp;D K Pal,&nbsp;C Sengupta","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Hansch analysis of some antimalarial cyclic peroxy ketals (IV) having structural variations at the para substituted phenyl ring and an alicyclic ring of different size reveals that electronic and steric parameters of the phenyl ring substituents are important for explaining the variation in the activity while hydrophobicity parameter is of little significance. Electron withdrawing substituents with higher MR (molar refractivity) or V(W) (van der Waals volume) are preferred for the activity. Use of structural descriptors suggests that presence of a seven membered alicyclic ring attached to the peroxy bridge containing ring is conducive to the activity. Application of electrotopological state atom index (ETSAI) suggests a pharmacophore containing the peroxy bridge. This is corroborated by earlier observation on importance of oxygen atoms of the peroxy linkage of artemisinin for antimalarial activity. Although incorporation of ETSAI into Hansch model does not improve the relations, the electronic parameter sigma is found to be significantly correlated with it.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"17 2","pages":"183-90"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21875713","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
Molecular modeling of 2-alkyloxy- and 2-aralkyloxy-adenosine A1- and A2-agonists. 2-烷基氧基和2-芳烷基氧基腺苷A1和a2激动剂的分子模拟。
Drug design and discovery Pub Date : 2000-01-01
M M Matova, R N Nacheva, S V Boicheva
{"title":"Molecular modeling of 2-alkyloxy- and 2-aralkyloxy-adenosine A1- and A2-agonists.","authors":"M M Matova,&nbsp;R N Nacheva,&nbsp;S V Boicheva","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The C2-region of adenosine A1- and A2-receptors by a molecular modeling technique has been extended and applied to a series of 2-substituted adenosines reported by Olsson, et al. The similarity and dissimilarity of the structure maps obtained by molecular modeling have been used as a basis for the mapping of the analysed receptor domain. The proposed model of the C2-region of the A1-receptor consists of a narrow and sterically limited area that interacts well electrostatically with small and electron rich moieties. Olsson's provisional model of the C2-region of the A2-receptor has been extended with two subsites, as well as with a forbidden area near the C2-position of the purine ring. The conformational analysis performed in the study does not support the hypothesis of Olsson et al. that adenosine C2 substituents may partly occupy the same receptor domain as the N6 substituents of the A1-receptor. The occupation of the cycloalkyl subsite increases the receptor selectivity while the occupation of the other subsite by aryl rings, fixed at a parallel position to the purine system, highly enhances the receptor affinity.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"16 4","pages":"255-70"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21654189","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
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