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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Structure-based design and optimization of potent renin inhibitors on 5- or 7-azaindole-scaffolds.
TL;DR: The optimization of two series of azaindoles to arrive at potent and non-chiral renin inhibitors results in the identification of novel 5- or 7-azaindole derivatives with remarkable potency for renin inhibition.
Journal ArticleDOI
Exploration of Novel Inhibitors for Class I Histone Deacetylase Isoforms by QSAR Modeling and Molecular Dynamics Simulation Assays
TL;DR: Overall, bioactivity and ligand efficiency (binding energy/non-hydrogen atoms) profiles suggested that proposed hits may be more effective inhibitors for cancer therapy.
Journal ArticleDOI
The role and impact of high throughput biomimetic measurements in drug discovery
Shenaz Bunally,Robert J. Young +1 more
TL;DR: An automated physchem platform is developed which ensures that consistent, comprehensive, and high-quality physicochemical property measurements and derived property information for 100's of compounds per week are available alongside potency data at the right time to guide compound progression decisions.
Journal ArticleDOI
Panel docking of small-molecule libraries — Prospects to improve efficiency of lead compound discovery
Pakornwit Sarnpitak,Prashant Mujumdar,Paul Taylor,Megan Cross,Mark J. Coster,Alain-Dominique Gorse,Mikhail Krasavin,Andreas Hofmann,Andreas Hofmann +8 more
TL;DR: By computationally screening a reasonably sized library of 1235 compounds against a panel of 48 mostly human kinases, this article is able to identify five groups of putative lead compounds with substantial diversity when compared to each other.
Journal ArticleDOI
Design and Synthesis of Potent and Selective PIM Kinase Inhibitors by Targeting Unique Structure of ATP-Binding Pocket.
TL;DR: This work sets out to improve the PIM (proviral integration site for Moloney murine leukemia virus) kinase-inhibitory selectivity of the previously reported 7-azaindole derivative 2, which has promising ADMET properties, by targeting a unique bulge in the ATP-binding pocket.
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.