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Journal ArticleDOI

The influence of drug-like concepts on decision-making in medicinal chemistry

01 Nov 2007-Nature Reviews Drug Discovery (Nature Publishing Group)-Vol. 6, Iss: 11, pp 881-890
TL;DR: Analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development.
Abstract: The application of guidelines linked to the concept of drug-likeness, such as the 'rule of five', has gained wide acceptance as an approach to reduce attrition in drug discovery and development. However, despite this acceptance, analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development. The consequences of the marked increase in lipophilicity--the most important drug-like physical property--include a greater likelihood of lack of selectivity and attrition in drug development. Tackling the threat of compound-related toxicological attrition needs to move to the mainstream of medicinal chemistry decision-making.
Citations
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Journal ArticleDOI
TL;DR: This tutorial review provides a sampling of renowned fluorinated drugs and their mode of action with a discussion clarifying the role and impact of fluorine substitution on drug potency.
Abstract: It has become evident that fluorinated compounds have a remarkable record in medicinal chemistry and will play a continuing role in providing lead compounds for therapeutic applications. This tutorial review provides a sampling of renowned fluorinated drugs and their mode of action with a discussion clarifying the role and impact of fluorine substitution on drug potency.

4,664 citations

Journal ArticleDOI
TL;DR: A new appreciation of the role of polypharmacology has significant implications for tackling the two major sources of attrition in drug development--efficacy and toxicity.
Abstract: The dominant paradigm in drug discovery is the concept of designing maximally selective ligands to act on individual drug targets. However, many effective drugs act via modulation of multiple proteins rather than single targets. Advances in systems biology are revealing a phenotypic robustness and a network structure that strongly suggests that exquisitely selective compounds, compared with multitarget drugs, may exhibit lower than desired clinical efficacy. This new appreciation of the role of polypharmacology has significant implications for tackling the two major sources of attrition in drug development--efficacy and toxicity. Integrating network biology and polypharmacology holds the promise of expanding the current opportunity space for druggable targets. However, the rational design of polypharmacology faces considerable challenges in the need for new methods to validate target combinations and optimize multiple structure-activity relationships while maintaining drug-like properties. Advances in these areas are creating the foundation of the next paradigm in drug discovery: network pharmacology.

2,915 citations


Cites background from "The influence of drug-like concepts..."

  • ...Analysis of the Bioprint database of the complete screening matrix of FDA-approved drugs against approximately 200 assays reveals a strong relationship between calculated lipophilicity ( c log P ) and low-affinity off-target promiscuit...

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Journal ArticleDOI
TL;DR: The reaction types used in the pursuit of novel drug candidates are analyzed to evaluate their frequency of occurrence, alongside other factors such as drug likeness, chirality, and the number of steps to each derivative.
Abstract: The Medicinal Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates

1,712 citations

Journal ArticleDOI
TL;DR: Analysis of rings, ring systems, and frameworks in drugs listed in the FDA Orange Book gives insight into the chemical novelty of drugs and potentially efficient ways to assess compound libraries and develop compounds from hit identification to lead optimization and beyond.
Abstract: We have analyzed the rings, ring systems, and frameworks in drugs listed in the FDA Orange Book to understand the frequency, timelines, molecular property space, and the application of these rings in different therapeutic areas and target classes. This analysis shows that there are only 351 ring systems and 1197 frameworks in drugs that came onto the market before 2013. Furthermore, on average six new ring systems enter drug space each year and approximately 28% of new drugs contain a new ring system. Moreover, it is very unusual for a drug to contain more than one new ring system and the majority of the most frequently used ring systems (83%) were first used in drugs developed prior to 1983. These observations give insight into the chemical novelty of drugs and potentially efficient ways to assess compound libraries and develop compounds from hit identification to lead optimization and beyond.

1,441 citations

Journal ArticleDOI
TL;DR: More comprehensive tracking of compounds from research stages through clinical development to market is provided through the inclusion of data from United States Adopted Name applications and a new richer data model for representing drug targets has been developed.
Abstract: ChEMBL is an open large-scale bioactivity database (https://www.ebi.ac.uk/chembl), previously described in the 2012 Nucleic Acids Research Database Issue. Since then, a variety of new data sources and improvements in functionality have contributed to the growth and utility of the resource. In particular, more comprehensive tracking of compounds from research stages through clinical development to market is provided through the inclusion of data from United States Adopted Name applications; a new richer data model for representing drug targets has been developed; and a number of methods have been put in place to allow users to more easily identify reliable data. Finally, access to ChEMBL is now available via a new Resource Description Framework format, in addition to the web-based interface, data downloads and web services.

1,302 citations


Cites background from "The influence of drug-like concepts..."

  • ...of the more common have now been made available in the database: Ligand Efficiency (LE) (28), Binding Efficiency Index (BEI), Surface Efficiency Index (SEI) (29) and Lipophilic Ligand Efficiency (LLE) (30)....

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  • ...There are a number of different measures now described in the literature and four of the more common have now been made available in the database: Ligand Efficiency (LE) (28), Binding Efficiency Index (BEI), Surface Efficiency Index (SEI) (29) and Lipophilic Ligand Efficiency (LLE) (30)....

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References
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Journal ArticleDOI
TL;DR: Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described in this article, where the rule of 5 is used to predict poor absorption or permeability when there are more than 5 H-bond donors, 10 Hbond acceptors, and the calculated Log P (CLogP) is greater than 5 (or MlogP > 415).

14,026 citations

Journal ArticleDOI
TL;DR: Reduced molecular flexibility, as measured by the number of rotatable bonds, and low polar surface area or total hydrogen bond count are found to be important predictors of good oral bioavailability, independent of molecular weight.
Abstract: Oral bioavailability measurements in rats for over 1100 drug candidates studied at SmithKline Beecham Pharmaceuticals (now GlaxoSmithKline) have allowed us to analyze the relative importance of molecular properties considered to influence that drug property. Reduced molecular flexibility, as measured by the number of rotatable bonds, and low polar surface area or total hydrogen bond count (sum of donors and acceptors) are found to be important predictors of good oral bioavailability, independent of molecular weight. That on average both the number of rotatable bonds and polar surface area or hydrogen bond count tend to increase with molecular weight may in part explain the success of the molecular weight parameter in predicting oral bioavailability. The commonly applied molecular weight cutoff at 500 does not itself significantly separate compounds with poor oral bioavailability from those with acceptable values in this extensive data set. Our observations suggest that compounds which meet only the two cr...

5,191 citations


"The influence of drug-like concepts..." refers background in this paper

  • ...Overall oral bioavailability depends not just on absorption but also on dissolution, gut transit time and first-pass metabolism, so it is perhaps surprising that rat bioavailability can be categorized by simple physical properties such as PSA and rotatable bond...

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Journal ArticleDOI
TL;DR: The pharmaceutical industry faces considerable challenges, both politically and fiscally, and the fiscal pressures that face the industry from the perspective of R&D are dealt with.
Abstract: The pharmaceutical industry faces considerable challenges, both politically and fiscally. Politically, governments around the world are trying to contain costs and, as health care budgets constitute a very significant part of governmental spending, these costs are the subject of intense scrutiny. In the United States, drug costs are also the subject of intense political discourse. This article deals with the fiscal pressures that face the industry from the perspective of R&D. What impinges on productivity? How can we improve current reduced R&D productivity?

3,746 citations

Book
01 Jan 1998
TL;DR: This CD-ROM provides the tools to draw structures and then search for them, and presents over 10,000 monographs which detail chemicals, drugs and biologicals, and describe a single substance or small group of related compounds.
Abstract: Presents over 10,000 monographs which detail chemicals, drugs and biologicals, and describe a single substance or small group of related compounds This CD-ROM provides the tools to draw structures and then search for them Users are able to access the data they need quickly with a choice of search options: text search, structure search, and sub-structure search Text searching is possible for every field of the database: chemical, common, generic and brand names; molecular weights and formulae; physical and toxicity data; and citations to the scientific and patent literature New with this release are organic name reactions available as a fully text searchable file, and 100 new monographs detailing the latest new drugs and compounds of recent interest This CD-ROM should be of interest to medicinal chemists, pharmaceutical chemists, biochemists, environmentalists, medical practitioners, natural product chemists, biologists, food scientists, pharmacologists, clinical chemists, organic chemists, inorganic chemists, and information professionals

3,577 citations

Journal ArticleDOI
Christopher A. Lipinski1
TL;DR: This topic is explored in terms ofDrug-like physicochemical features, drug-like structural features, a comparison of drug- like and non-drug-like in drug discovery and a discussion of how drug-Like features relate to clinical success.

3,499 citations


"The influence of drug-like concepts..." refers background in this paper

  • ...jpg" NDATA ITEM> ]> Ten years have passed since the publication of the 'rule of five' physical property guidelines for drug permeabilit...

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