Journal ArticleDOI
The influence of drug-like concepts on decision-making in medicinal chemistry
TLDR
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.read more
Citations
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Fluorine in medicinal chemistry.
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.
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Network pharmacology: the next paradigm in drug discovery.
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.
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The Medicinal Chemist's Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates
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.
Journal ArticleDOI
Rings in Drugs
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.
Journal ArticleDOI
The ChEMBL bioactivity database: an update
A. Patrícia Bento,Anna Gaulton,Anne Hersey,Louisa J. Bellis,Jon Chambers,Mark Davies,Felix A. Kruger,Yvonne Light,Lora Mak,Shaun McGlinchey,Michal Nowotka,George Papadatos,Rita Santos,John P. Overington +13 more
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.
References
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Journal ArticleDOI
Property-based design: optimization of drug absorption and pharmacokinetics.
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A bioavailability score.
TL;DR: This work has developed a score that assigns the probability that a compound will have F > 10% in the rat, and distinguishes compounds that are poorly permeable from those that are permeable in Caco-2 cells.
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A comparison of physiochemical property profiles of development and marketed oral drugs.
TL;DR: A study in which the distributions of physiochemical properties of oral drugs in different phases of clinical development are compared to those already marketed, showing that the mean molecular weight of orally administered drugs in development decreases on passing through each of the different clinical phases and gradually converges toward the mean Molecular weight of marketed oral drugs.
Journal ArticleDOI
Druggability indices for protein targets derived from NMR-based screening data.
TL;DR: An analysis of heteronuclear-NMR-based screening data is used to derive relationships between the ability of small molecules to bind to a protein and various parameters that describe the protein binding site and these allow for quantitative comparative analyses of protein binding sites for use in target assessment and validation, virtual ligand screening, and structure-based drug design.
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Can we rationally design promiscuous drugs
TL;DR: Recent advances in post-genomic biology are indicating that polypharmacology may be a necessary trait for the efficacy of many drugs, therefore questioning the "one drug, one target" assumption of current rational drug design.