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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Journal ArticleDOI
Application of Negative Design To Design a More Desirable Virtual Screening Library.
TL;DR: In this review, the advances in negative design for the evaluations of drug-likeness, frequent hitters and toxicity are outlined and the related web servers and software packages developed recently for negative design are summarized.
Journal ArticleDOI
The Flip-Flop Diffusion Mechanism across Lipids in a Hybrid Bilayer Membrane.
Christopher J. Barile,Edmund C. M. Tse,Ying Li,John P. Gewargis,Nicholas A. Kirchschlager,Steven C. Zimmerman,Andrew A. Gewirth,Andrew A. Gewirth +7 more
TL;DR: A detailed mechanism for transmembrane flip-flop diffusion in HBM systems, which involves the bending of the alkyl tail of the proton carrier as the rate-determining step is proposed.
Journal ArticleDOI
Synthesis and biological evaluation of (E)-4-(3-arylvinyl-1H-indazol-6-yl)pyrimidin-2-amine derivatives as PLK4 inhibitors for the treatment of breast cancer
Zhihao Liu,Qian Lei,Wei Wei,Lu Xiong,Yao-Jie Shi,Guoyi Yan,Chao Gao,Tinghong Ye,Ningyu Wang,Luoting Yu +9 more
TL;DR: (E)-4-(3-arylvinyl-1H-indazol-6-yl)pyrimidin-2-amine derivatives as potent PLK4 inhibitors with more concise structure using a scaffold hopping strategy are described.
Journal ArticleDOI
Covalent Organic Frameworks toward Diverse Photocatalytic Aerobic Oxidations.
TL;DR: In this paper, a visible-light-driven selective aerobic oxidation of various small organic molecules by using photoactive two-dimensional covalent organic frameworks (2D-COFs) as the photocatalyst was developed.
Journal ArticleDOI
Polycomb Repressive Complex 2 Modulation through the Development of EZH2-EED Interaction Inhibitors and EED Binders.
TL;DR: In this article, the authors summarize the latest findings regarding the development and the biological activity of these emerging classes of PRC2 modulators from a medicinal chemist's viewpoint, and summarize their biological activity.
References
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Journal ArticleDOI
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
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).
Journal ArticleDOI
Molecular properties that influence the oral bioavailability of drug candidates.
Daniel F. Veber,Stephen R. Johnson,Hung-Yuan Cheng,Brian R. Smith,Keith W. Ward,Kenneth D. Kopple +5 more
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.
Journal ArticleDOI
Can the pharmaceutical industry reduce attrition rates
Ismail Kola,John Landis +1 more
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.
Book
The Merck index
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.
Journal ArticleDOI
Lead- and drug-like compounds: the rule-of-five revolution.
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.