{"title":"了解你的分子:候选药物的药理学特征,以提高疗效并减少后期损耗。","authors":"Terry Kenakin","doi":"10.1038/s41573-024-00958-9","DOIUrl":null,"url":null,"abstract":"Despite advances in chemical, computational and biological sciences, the rate of attrition of drug candidates in clinical development is still high. A key point in the small-molecule discovery process that could provide opportunities to help address this challenge is the pharmacological characterization of hit and lead compounds, culminating in the selection of a drug candidate. Deeper characterization is increasingly important, because the ‘quality’ of drug efficacy, at least for G protein-coupled receptors (GPCRs), is now understood to be much more than activation of commonly evaluated pathways such as cAMP signalling, with many more ‘efficacies’ of ligands that could be harnessed therapeutically. Such characterization is being enabled by novel assays to characterize the complex behaviour of GPCRs, such as biased signalling and allosteric modulation, as well as advances in structural biology, such as cryo-electron microscopy. This article discusses key factors in the assessments of the pharmacology of hit and lead compounds in the context of GPCRs as a target class, highlighting opportunities to identify drug candidates with the potential to address limitations of current therapies and to improve the probability of them succeeding in clinical development. Deeper pharmacological characterization of hit and lead compounds is being enabled by novel assays to characterize target behaviour as well as by advances in structural biology. This article discusses key factors in pharmacological characterization in the context of G protein-coupled receptors as a target class, highlighting opportunities to identify drug candidates with the potential to address limitations of current therapies and to increase the probability of them succeeding in clinical trials.","PeriodicalId":19068,"journal":{"name":"Nature Reviews. 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Deeper characterization is increasingly important, because the ‘quality’ of drug efficacy, at least for G protein-coupled receptors (GPCRs), is now understood to be much more than activation of commonly evaluated pathways such as cAMP signalling, with many more ‘efficacies’ of ligands that could be harnessed therapeutically. Such characterization is being enabled by novel assays to characterize the complex behaviour of GPCRs, such as biased signalling and allosteric modulation, as well as advances in structural biology, such as cryo-electron microscopy. This article discusses key factors in the assessments of the pharmacology of hit and lead compounds in the context of GPCRs as a target class, highlighting opportunities to identify drug candidates with the potential to address limitations of current therapies and to improve the probability of them succeeding in clinical development. 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Know your molecule: pharmacological characterization of drug candidates to enhance efficacy and reduce late-stage attrition
Despite advances in chemical, computational and biological sciences, the rate of attrition of drug candidates in clinical development is still high. A key point in the small-molecule discovery process that could provide opportunities to help address this challenge is the pharmacological characterization of hit and lead compounds, culminating in the selection of a drug candidate. Deeper characterization is increasingly important, because the ‘quality’ of drug efficacy, at least for G protein-coupled receptors (GPCRs), is now understood to be much more than activation of commonly evaluated pathways such as cAMP signalling, with many more ‘efficacies’ of ligands that could be harnessed therapeutically. Such characterization is being enabled by novel assays to characterize the complex behaviour of GPCRs, such as biased signalling and allosteric modulation, as well as advances in structural biology, such as cryo-electron microscopy. This article discusses key factors in the assessments of the pharmacology of hit and lead compounds in the context of GPCRs as a target class, highlighting opportunities to identify drug candidates with the potential to address limitations of current therapies and to improve the probability of them succeeding in clinical development. Deeper pharmacological characterization of hit and lead compounds is being enabled by novel assays to characterize target behaviour as well as by advances in structural biology. This article discusses key factors in pharmacological characterization in the context of G protein-coupled receptors as a target class, highlighting opportunities to identify drug candidates with the potential to address limitations of current therapies and to increase the probability of them succeeding in clinical trials.
期刊介绍:
Nature Reviews Drug Discovery is a monthly journal aimed at everyone working in the drug discovery and development arena.
Each issue includes:
Highest-quality reviews and perspectives covering a broad scope.
News stories investigating the hottest topics in drug discovery.
Timely summaries of key primary research papers.
Concise updates on the latest advances in areas such as new drug approvals, patent law, and emerging industry trends and strategies.