Pub Date : 2017-08-04DOI: 10.2174/97816810858211180901
Atta- ur-Rahman
{"title":"Frontiers in Drug Design & Discovery, Volume 9","authors":"Atta- ur-Rahman","doi":"10.2174/97816810858211180901","DOIUrl":"https://doi.org/10.2174/97816810858211180901","url":null,"abstract":"","PeriodicalId":437469,"journal":{"name":"Frontiers in Drug Design & Discovery","volume":"5 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2017-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114163420","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}
Pub Date : 2010-02-03DOI: 10.2174/978160805203511005010146
M. Moos
{"title":"Enabling drug delivery to cancer cells and tumor endothelium: the benefit of targeted therapy","authors":"M. Moos","doi":"10.2174/978160805203511005010146","DOIUrl":"https://doi.org/10.2174/978160805203511005010146","url":null,"abstract":"","PeriodicalId":437469,"journal":{"name":"Frontiers in Drug Design & Discovery","volume":"132 5 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2010-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124254228","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}
Pub Date : 2009-12-13DOI: 10.2174/978160805202810904010097
H. Ishiguro, I. Yano, M. Toi
{"title":"Important Drug Interactions for Clinical Oncologists","authors":"H. Ishiguro, I. Yano, M. Toi","doi":"10.2174/978160805202810904010097","DOIUrl":"https://doi.org/10.2174/978160805202810904010097","url":null,"abstract":"","PeriodicalId":437469,"journal":{"name":"Frontiers in Drug Design & Discovery","volume":"54 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2009-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115176151","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}
Pub Date : 2009-12-13DOI: 10.2174/978160805202810904010122
H. Ishiguro, I. Yano, M. Toi
{"title":"Pharmacogenomic considerations in breast cancer management","authors":"H. Ishiguro, I. Yano, M. Toi","doi":"10.2174/978160805202810904010122","DOIUrl":"https://doi.org/10.2174/978160805202810904010122","url":null,"abstract":"","PeriodicalId":437469,"journal":{"name":"Frontiers in Drug Design & Discovery","volume":"15 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2009-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122137206","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}
Pub Date : 2009-12-13DOI: 10.2174/978160805202810904010135
Alexandra S. Bause, Sarah D. Lamore, G. Wondrak
{"title":"More Than Skin Deep: The Human Skin Tissue Equivalent as an Advanced Drug Discovery Tool","authors":"Alexandra S. Bause, Sarah D. Lamore, G. Wondrak","doi":"10.2174/978160805202810904010135","DOIUrl":"https://doi.org/10.2174/978160805202810904010135","url":null,"abstract":"","PeriodicalId":437469,"journal":{"name":"Frontiers in Drug Design & Discovery","volume":"4 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2009-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131125775","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}
Pub Date : 2007-12-13DOI: 10.2174/978160805201110703010559
M. Dascombe, M. Drew, Philip G. Evans, Fyaz M. D. Ismail
The evolution and subsequent design of clinically effective antima- larial drugs particularly 4-aminoquinolines, 8-aminoquinolines and 9-amino- acridines are reviewed. These molecules benefited from scientific advances in medicinal and synthetic chemistry guided by pharmacological screening, inc- luding animal models of malaria. The mechanism of action of antimalarials, especially against the heme receptor, and the impact of this knowledge on drug design is critically discussed. Modelling investigations and quantum mecha- nics calculations reveal close contacts between the porphyrin ring and selected atoms within compounds such as the bisquinoline, metaquine. Analysis of the- se close contacts can be used to design compounds with modulated antimalari- al activity to further clarify the drug action. Knowledge of mammalian drug metabolism and pharmacokinetics, together with detailed in vitro and in vivo pharmacology has aided (a) resurrection of old compounds and (b) redesign of existing compounds. The latter includes judicious modification (e.g. inversion of oxidizable functional groups as in SN-13,730 i.e. isoquine) or introduction of groups blocking metabolism (e.g. exploiting bond strength viz. fluorine or steric effects with the t-butyl group). This simultaneous modulation of both drug metabolism and interaction with the heme receptor can be used to enhan- ce antimalarial activity. Compounds benefiting from such modifications inclu- de primaquine, pyronaridine, isoquine, metaquine and AQ-13, together with selected analogues with useful activity against drug-resistant Plasmodia in vi- vo. It is concluded that optimisation of the privileged quinoline and acridine scaffolds, discovered in the early part of the 20 th century, still has a vital role to play in the future discovery of cost effective solutions to malaria.
{"title":"Rational Design Strategies for the Development of Synthetic Quinoline and Acridine Based Antimalarials","authors":"M. Dascombe, M. Drew, Philip G. Evans, Fyaz M. D. Ismail","doi":"10.2174/978160805201110703010559","DOIUrl":"https://doi.org/10.2174/978160805201110703010559","url":null,"abstract":"The evolution and subsequent design of clinically effective antima- larial drugs particularly 4-aminoquinolines, 8-aminoquinolines and 9-amino- acridines are reviewed. These molecules benefited from scientific advances in medicinal and synthetic chemistry guided by pharmacological screening, inc- luding animal models of malaria. The mechanism of action of antimalarials, especially against the heme receptor, and the impact of this knowledge on drug design is critically discussed. Modelling investigations and quantum mecha- nics calculations reveal close contacts between the porphyrin ring and selected atoms within compounds such as the bisquinoline, metaquine. Analysis of the- se close contacts can be used to design compounds with modulated antimalari- al activity to further clarify the drug action. Knowledge of mammalian drug metabolism and pharmacokinetics, together with detailed in vitro and in vivo pharmacology has aided (a) resurrection of old compounds and (b) redesign of existing compounds. The latter includes judicious modification (e.g. inversion of oxidizable functional groups as in SN-13,730 i.e. isoquine) or introduction of groups blocking metabolism (e.g. exploiting bond strength viz. fluorine or steric effects with the t-butyl group). This simultaneous modulation of both drug metabolism and interaction with the heme receptor can be used to enhan- ce antimalarial activity. Compounds benefiting from such modifications inclu- de primaquine, pyronaridine, isoquine, metaquine and AQ-13, together with selected analogues with useful activity against drug-resistant Plasmodia in vi- vo. It is concluded that optimisation of the privileged quinoline and acridine scaffolds, discovered in the early part of the 20 th century, still has a vital role to play in the future discovery of cost effective solutions to malaria.","PeriodicalId":437469,"journal":{"name":"Frontiers in Drug Design & Discovery","volume":"66 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2007-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133189957","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}
Pub Date : 2006-12-13DOI: 10.2174/978160805200410602010259
M. Riley, Iram Mondaca Fernandez, P. Lucas
{"title":"Spectroscopic Analysis of Cell Physiology and Function","authors":"M. Riley, Iram Mondaca Fernandez, P. Lucas","doi":"10.2174/978160805200410602010259","DOIUrl":"https://doi.org/10.2174/978160805200410602010259","url":null,"abstract":"","PeriodicalId":437469,"journal":{"name":"Frontiers in Drug Design & Discovery","volume":"29 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2006-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122138064","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}
Pub Date : 2006-12-13DOI: 10.2174/978160805200410602010333
S. Krol, A. Gliozzi, A. Diaspro
{"title":"Polyelectrolyte Nanocapsules - Promising Progress in Development of New Drugs and Therapies","authors":"S. Krol, A. Gliozzi, A. Diaspro","doi":"10.2174/978160805200410602010333","DOIUrl":"https://doi.org/10.2174/978160805200410602010333","url":null,"abstract":"","PeriodicalId":437469,"journal":{"name":"Frontiers in Drug Design & Discovery","volume":"39 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2006-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116475071","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}
Pub Date : 2005-12-13DOI: 10.2174/1574088054583381
R. Eglen
Technologies used for high throughput screening (HTS) at G protein coupled receptors (GPCRs) comprise two major approaches; those generally conducted measuring signal intensity changes using a microtiter plate format, and those measuring cellular protein redistribution via imaging-based analysis systems. Several homogeneous assays, i.e. those without wash and fluid phase separation steps, measure changes of second messenger signaling molecules including cAMP, Ins P3 and calcium. Imaging based assays determined the translocation of GPCR associated proteins such as β arrestin, or internalization of the receptor labeled with fusion tags. Generally, the former assays are used in a primary screening campaign, whilst the latter are used in secondary screening and lead optimization. However, increasing use of automated confocal imaging systems and prevalence of modified cell lines has expanded use of protein redistribution assays. Finally, radiometric techniques are widely used, frequently to measure GPCR ligand binding, using a scintillation proximity assay format. In this paper, the various assay methods used for HTS at G protein coupled receptors are compared and contrasted. G PROTEIN COUPLED RECEPTORS AND HIGH THROUGHPUT SCREENING G protein coupled receptors (GPCRs) are a proven class of targets for drug discovery and are frequent targets entering high throughput screening (HTS) laboratories. Modern HTS is a highly automated approach to compound identification using robotic, fluid dispensing systems and sensitive signal detection instruments [1]. Several assay techniques for GPCR screening employ non-radiometric assay platforms. Radiometric techniques dominate in assays in which ligand binding to the GPCR per se is measured, [2]. There is increased adoption of functional assays in which the effects of the activated GPCR on function are determined, with concomitant development and implementation of cell based assay technologies, and automated cell culture and dispensing [3]. Compounds active at GPCRs have therapeutic benefit in many diseases ranging from central nervous system disorders, including pain, schizophrenia and depression, and metabolic disorders, such as cancer, obesity or diabetes [5]. GPCRs are considered a highly ‘druggable’ class of proteins, with over 40% of marketed drugs (such as Zyprexa, Clarinex, Zantac and Zelnorm) acting to modulate their function. Interestingly, approximately 9% of global pharmaceutical sales are realized from drugs targeted *Corresponding author: Tel: 510 979 1415 x 103; Fax: 510 979 1650; E-mail: reglen@discoverx.com 98 Frontiers in Drug Design & Discovery, 2005, Vol. 1 Richard M. Eglen against only 40-50 well-characterized GPCRs. As there are between 800-1000 genes in the human genome belonging to the GPCR superfamily, it is likely that many more GPCRs remain to be validated as drug targets. Furthermore, endogenous ligands have been identified for only 200 GPCRs, even though the human genome contains many mo
{"title":"An Overview of High Throughput Screening at G Protein Coupled Receptors","authors":"R. Eglen","doi":"10.2174/1574088054583381","DOIUrl":"https://doi.org/10.2174/1574088054583381","url":null,"abstract":"Technologies used for high throughput screening (HTS) at G protein coupled receptors (GPCRs) comprise two major approaches; those generally conducted measuring signal intensity changes using a microtiter plate format, and those measuring cellular protein redistribution via imaging-based analysis systems. Several homogeneous assays, i.e. those without wash and fluid phase separation steps, measure changes of second messenger signaling molecules including cAMP, Ins P3 and calcium. Imaging based assays determined the translocation of GPCR associated proteins such as β arrestin, or internalization of the receptor labeled with fusion tags. Generally, the former assays are used in a primary screening campaign, whilst the latter are used in secondary screening and lead optimization. However, increasing use of automated confocal imaging systems and prevalence of modified cell lines has expanded use of protein redistribution assays. Finally, radiometric techniques are widely used, frequently to measure GPCR ligand binding, using a scintillation proximity assay format. In this paper, the various assay methods used for HTS at G protein coupled receptors are compared and contrasted. G PROTEIN COUPLED RECEPTORS AND HIGH THROUGHPUT SCREENING G protein coupled receptors (GPCRs) are a proven class of targets for drug discovery and are frequent targets entering high throughput screening (HTS) laboratories. Modern HTS is a highly automated approach to compound identification using robotic, fluid dispensing systems and sensitive signal detection instruments [1]. Several assay techniques for GPCR screening employ non-radiometric assay platforms. Radiometric techniques dominate in assays in which ligand binding to the GPCR per se is measured, [2]. There is increased adoption of functional assays in which the effects of the activated GPCR on function are determined, with concomitant development and implementation of cell based assay technologies, and automated cell culture and dispensing [3]. Compounds active at GPCRs have therapeutic benefit in many diseases ranging from central nervous system disorders, including pain, schizophrenia and depression, and metabolic disorders, such as cancer, obesity or diabetes [5]. GPCRs are considered a highly ‘druggable’ class of proteins, with over 40% of marketed drugs (such as Zyprexa, Clarinex, Zantac and Zelnorm) acting to modulate their function. Interestingly, approximately 9% of global pharmaceutical sales are realized from drugs targeted *Corresponding author: Tel: 510 979 1415 x 103; Fax: 510 979 1650; E-mail: reglen@discoverx.com 98 Frontiers in Drug Design & Discovery, 2005, Vol. 1 Richard M. Eglen against only 40-50 well-characterized GPCRs. As there are between 800-1000 genes in the human genome belonging to the GPCR superfamily, it is likely that many more GPCRs remain to be validated as drug targets. Furthermore, endogenous ligands have been identified for only 200 GPCRs, even though the human genome contains many mo","PeriodicalId":437469,"journal":{"name":"Frontiers in Drug Design & Discovery","volume":"23 2 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2005-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129607543","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}
Pub Date : 2005-12-13DOI: 10.2174/1574088054583390
Cheng-Pang Hsu, G. Caldwell, J. Masucci, Zhengyin Yan, D. Ritchie
{"title":"Assessment of iDEA pkEXPRESS™ for The Prediction of Caco-2 Permeabilities","authors":"Cheng-Pang Hsu, G. Caldwell, J. Masucci, Zhengyin Yan, D. Ritchie","doi":"10.2174/1574088054583390","DOIUrl":"https://doi.org/10.2174/1574088054583390","url":null,"abstract":"","PeriodicalId":437469,"journal":{"name":"Frontiers in Drug Design & Discovery","volume":"14 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2005-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126795230","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}
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