Cyclophilin A (CypA) is a ubiquitous cellular enzyme playing essential role in many biological processes, and the discovery of CypA inhibitor is now of special interest in the treatment of immunological disorders. In this work, molecular modeling studies were performed to develop a predictive Common Pharmacophore Hypothesis (CPH) and use it for alignment in 3D-QSAR studies using CoMFA and CoMSIA. A total of 30 compounds containing an amide fragment as the key linker, consisting of 17 of our previously discovered CypA inhibitors and 13 other inhibitors reported in the literature, were selected for pharmacophore refinement and 3D-QSAR studies. The best pharmacophore hypothesis AADR, which had two hydrogen bond acceptors, a hydrogen bond donor, and an aromatic ring, was obtained and used for the alignment of molecules in CoMFA and CoMSIA model development. The models showed a good r2 value of 0.992 and 0.949 for CoMFA and CoMSIA, respectively. The contour maps of the models were analyzed to give structural insight for activity improvement of future novel CypA inhibitors. The CPH can also provide a powerful template for virtual screening and design of new CypA inhibitors.
{"title":"Refinement and 3D-QSAR Studies of Inhibitors of Cyclophilin A Containing Amide Linker.","authors":"Feng Fan, Jin Zhu, Shuaishuai Ni, Jiagao Cheng, Yun Tang, Congmin Kang, Jian Li, Hualiang Jiang","doi":"10.1002/qsar.200860076","DOIUrl":"10.1002/qsar.200860076","url":null,"abstract":"<p><p>Cyclophilin A (CypA) is a ubiquitous cellular enzyme playing essential role in many biological processes, and the discovery of CypA inhibitor is now of special interest in the treatment of immunological disorders. In this work, molecular modeling studies were performed to develop a predictive Common Pharmacophore Hypothesis (CPH) and use it for alignment in 3D-QSAR studies using CoMFA and CoMSIA. A total of 30 compounds containing an amide fragment as the key linker, consisting of 17 of our previously discovered CypA inhibitors and 13 other inhibitors reported in the literature, were selected for pharmacophore refinement and 3D-QSAR studies. The best pharmacophore hypothesis AADR, which had two hydrogen bond acceptors, a hydrogen bond donor, and an aromatic ring, was obtained and used for the alignment of molecules in CoMFA and CoMSIA model development. The models showed a good <i>r</i> <sup>2</sup> value of 0.992 and 0.949 for CoMFA and CoMSIA, respectively. The contour maps of the models were analyzed to give structural insight for activity improvement of future novel CypA inhibitors. The CPH can also provide a powerful template for virtual screening and design of new CypA inhibitors.</p>","PeriodicalId":49134,"journal":{"name":"Quantitative Structure-Activity Relationships & Combinatorial Science","volume":"28 2","pages":"183-193"},"PeriodicalIF":0.0,"publicationDate":"2009-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/qsar.200860076","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37866694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-11-01Epub Date: 2006-11-08DOI: 10.1002/qsar.200660012
Title: Traceless solid-phase synthesis of 3-substituted isoxazoles and 3-substituted 5-iodoisoxazolines using polystyrene-supported vinyl selenide. Authors: Sheng, S.-R.;* Xin, Q.; Liu, X.-L.; Sun, W.-K.; Guo, R.; Huang, X. Jiangxi Normal University, China Source: Synthesis 2006, 2293 – 2296. Significance: Vinylselenide resin underwent cycloaddition with nitrile oxides to give isoxazolines. Resin cleavage was achieved either under oxidative or alkylative conditions to give the oxazoline and iodo-isoxazoline respectively.
{"title":"Literature Highlights in Combinatorial Science: Solid-phase Synthesis.","authors":"","doi":"10.1002/qsar.200660012","DOIUrl":"https://doi.org/10.1002/qsar.200660012","url":null,"abstract":"Title: Traceless solid-phase synthesis of 3-substituted isoxazoles and 3-substituted 5-iodoisoxazolines using polystyrene-supported vinyl selenide. Authors: Sheng, S.-R.;* Xin, Q.; Liu, X.-L.; Sun, W.-K.; Guo, R.; Huang, X. Jiangxi Normal University, China Source: Synthesis 2006, 2293 – 2296. Significance: Vinylselenide resin underwent cycloaddition with nitrile oxides to give isoxazolines. Resin cleavage was achieved either under oxidative or alkylative conditions to give the oxazoline and iodo-isoxazoline respectively.","PeriodicalId":49134,"journal":{"name":"Quantitative Structure-Activity Relationships & Combinatorial Science","volume":"25 11","pages":"1123-1125"},"PeriodicalIF":0.0,"publicationDate":"2006-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/qsar.200660012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37866750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2005-11-01Epub Date: 2005-11-22DOI: 10.1002/qsar.200590050
Title: Heterogeneous hydrogenation reactions using a continuous flow high pressure device. Authors: Desai, B.; Kappe, C. O.* Graz University, Austria Source: J. Comb. Chem. 2005, 7, 641 – 643 Significance: A 'H-cube* apparatus was used in heterogeneous hydrogenation under continuous flow conditions. With dihydropyrimidines obtained from the Biginelli condensation, nitro reduction, benzyl ester deprotection and Raney nickel desulfurization were all demonstrated. Products were prepared in > 100 mg scale in 30 minutes.
{"title":"Literature Highlights in Combinatorial Science: QSAR Comb. Sci. 9/2005.","authors":"","doi":"10.1002/qsar.200590050","DOIUrl":"https://doi.org/10.1002/qsar.200590050","url":null,"abstract":"Title: Heterogeneous hydrogenation reactions using a continuous flow high pressure device. Authors: Desai, B.; Kappe, C. O.* Graz University, Austria Source: J. Comb. Chem. 2005, 7, 641 – 643 Significance: A 'H-cube* apparatus was used in heterogeneous hydrogenation under continuous flow conditions. With dihydropyrimidines obtained from the Biginelli condensation, nitro reduction, benzyl ester deprotection and Raney nickel desulfurization were all demonstrated. Products were prepared in > 100 mg scale in 30 minutes.","PeriodicalId":49134,"journal":{"name":"Quantitative Structure-Activity Relationships & Combinatorial Science","volume":"24 9","pages":"1117-1121"},"PeriodicalIF":0.0,"publicationDate":"2005-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/qsar.200590050","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37866749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2004-02-01Epub Date: 2004-02-18DOI: 10.1002/qsar.200330844
Haifeng Chen, Qiang Li, Xiaojun Yao, BoTao Fan, Shengang Yuan, A Panaye, J P Doucet
The intermolecular interaction between four types of anti-inflammatory inhibitors (oxazoles, pyrazoles, pyrroles and imidazoles) and COX-2 receptor was studied. The results of docking suggest that they have similar interaction mechanism. The most active compounds of these four types of inhibitors could both form several hydrogen bonds with residues His90, Arg513, Leu352 and Arg120, and develop hydrophobic interaction with residues Phe518, Leu352 and Leu359. This is consistent with the investigation reported by R. G. Kurumbail et al. (Nature.1996, 384, 644-648). A common 3D-QSAR model could be constructed with these four categories of COX-2 inhibitors using the method of docking- guided conformer selection. The cross-validated q2 values are found as 0.741 and 0.632 for CoMFA and CoMSIA respectively. And the non-cross-validated r2 values are 0.887 and 0.885. 54 inhibitors constitute the test set used to validate the model. The results show that this model possesses good predictive ability for diverse COX-2 inhibitors. Furthermore, a HQSAR model was used to evaluate the influence of substituents on anti-inflammatory activity. Compared with the results of previous works, our model possesses significantly better prediction ability. It could help us to well understand the interaction mechanism between inhibitors and COX-2 receptor, and to make quantitative prediction of their inhibitory activities.
{"title":"CoMFA/CoMSIA/HQSAR and Docking Study of the Binding Mode of Selective Cyclooxygenase (COX-2) Inhibitors.","authors":"Haifeng Chen, Qiang Li, Xiaojun Yao, BoTao Fan, Shengang Yuan, A Panaye, J P Doucet","doi":"10.1002/qsar.200330844","DOIUrl":"10.1002/qsar.200330844","url":null,"abstract":"<p><p>The intermolecular interaction between four types of anti-inflammatory inhibitors (oxazoles, pyrazoles, pyrroles and imidazoles) and COX-2 receptor was studied. The results of docking suggest that they have similar interaction mechanism. The most active compounds of these four types of inhibitors could both form several hydrogen bonds with residues His90, Arg513, Leu352 and Arg120, and develop hydrophobic interaction with residues Phe518, Leu352 and Leu359. This is consistent with the investigation reported by R. G. Kurumbail <i>et al.</i> (<i>Nature.</i> <b>1996</b>, 384, 644-648). A common 3D-QSAR model could be constructed with these four categories of COX-2 inhibitors using the method of docking- guided conformer selection. The cross-validated q<sup>2</sup> values are found as 0.741 and 0.632 for CoMFA and CoMSIA respectively. And the non-cross-validated r<sup>2</sup> values are 0.887 and 0.885. 54 inhibitors constitute the test set used to validate the model. The results show that this model possesses good predictive ability for diverse COX-2 inhibitors. Furthermore, a HQSAR model was used to evaluate the influence of substituents on anti-inflammatory activity. Compared with the results of previous works, our model possesses significantly better prediction ability. It could help us to well understand the interaction mechanism between inhibitors and COX-2 receptor, and to make quantitative prediction of their inhibitory activities.</p>","PeriodicalId":49134,"journal":{"name":"Quantitative Structure-Activity Relationships & Combinatorial Science","volume":"23 1","pages":"36-55"},"PeriodicalIF":0.0,"publicationDate":"2004-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168538/pdf/QSAR-23-36.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37866748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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