NDLI: Probing the links between in vitro potency, ADMET and physicochemical parameters.

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Probing the links between in vitro potency, ADMET and physicochemical parameters.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Gleeson, M. Paul Hersey, Anne Montanari, Dino Overington, John
Description	Country affiliation: Thailand Author Affiliation: Gleeson MP ( The Department of Chemistry, Faculty of Science, Kasetsart University, 50 Phaholyothin Road, Chatuchak, Bangkok 10900, Thailand. paul.gleeson@ku.ac.th)
Abstract	A common underlying assumption in current drug discovery strategies is that compounds with higher in vitro potency at their target(s) have greater potential to translate into successful, low-dose therapeutics. This has led to the development of screening cascades with in vitro potency embedded as an early filter. However, this approach is beginning to be questioned, given the bias in physicochemical properties that it can introduce early in lead generation and optimization, which is due to the often diametrically opposed relationship between physicochemical parameters associated with high in vitro potency and those associated with desirable absorption, distribution, metabolism, excretion and toxicity (ADMET) characteristics. Here, we describe analyses that probe these issues further using the ChEMBL database, which includes more than 500,000 drug discovery and marketed oral drug compounds. Key findings include: first, that oral drugs seldom possess nanomolar potency (50 nM on average); second, that many oral drugs have considerable off-target activity; and third, that in vitro potency does not correlate strongly with the therapeutic dose. These findings suggest that the perceived benefit of high in vitro potency may be negated by poorer ADMET properties.
File Format	HTM / HTML
ISSN	14741776
Issue Number	3
Volume Number	10
e-ISSN	14741784
Journal	Nature Reviews Drug Discovery
Language	English
Publisher	Nature Publishing Group
Publisher Date	2011-03-01
Publisher Place	Great Britain (UK)
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Discipline Pharmacology Discipline Biotechnology Drug Discovery Drug Therapy Pharmaceutical Preparations Metabolism Administration, Oral Animals Biotransformation Chemistry, Physical Drug-related Side Effects And Adverse Reactions Humans Chemistry Pharmacokinetics Receptors, Drug Substrate Specificity Tissue Distribution Journal Article Research Support, Non-u.s. Gov't Review
Content Type	Text
Resource Type	Article
Subject	Medicine Drug Discovery Pharmacology

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