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
Offline preparative 2-D polar-copolymerized reversed-phase chromatography × zwitterionic hydrophilic interaction chromatography for effective purification of polar compounds from Caulis Polygoni Multiflori
TL;DR: In this paper, an offline orthogonal 2-D RPLC coupled with hydrophilic interaction chromatography (HILIC) method was developed to achieve purification of polar compounds from Caulis polygoni multiflori.
Journal ArticleDOI
Identification of a novel conformationally constrained glucagon receptor antagonist.
Esther C.Y. Lee,Meihua Tu,Benjamin D. Stevens,Jianwei Bian,Gary Erik Aspnes,Christian Perreault,Matthew F. Sammons,Stephen W. Wright,John Litchfield,Amit S. Kalgutkar,Raman Sharma,Mary Theresa Didiuk,David Christopher Ebner,Kevin J. Filipski,Janice A. Brown,Karen Atkinson,Jeffrey A. Pfefferkorn,Angel Guzman-Perez +17 more
TL;DR: Novel glucagon receptor antagonists are identified via conformational constraint of current existing literature antagonists through optimization of lipophilic ligand efficiency, which culminated in enantiomers (+)-trans-26 and (--trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles.
Journal ArticleDOI
Novel azo pyridone dyes based on dihydropyrimidinone skeleton: Synthesis, DFT study and anticancer activity
Julijana Tadić,Jelena Lađarević,Željko J. Vitnik,Vesna D. Vitnik,Tatjana Stanojković,Ivana Z. Matić,Dušan Ž. Mijin +6 more
TL;DR: In silico evaluation of physicochemical parameters, druglikeness and ADME properties showed that investigated compounds are orally bioavailable with no permeation to the blood brain barrier.
Journal ArticleDOI
Partitioning into Colloidal Structures of Fasted State Intestinal Fluid Studied by Molecular Dynamics Simulations.
TL;DR: Important intermolecular interactions in lipidic bilayers are revealed, both between the bile components themselves and with the drug molecules, indicating that the incorporation of TCH plays a crucial role for the partitioning of lipophilic solutes into e.g. lipidic vesicles existing in fasted state intestinal fluids.
Journal ArticleDOI
Analysis of solvent-exposed and buried co-crystallized ligands: a case study to support the design of novel protein-protein interaction inhibitors.
Daniela Trisciuzzi,Orazio Nicolotti,Maria A. Miteva,Bruno O. Villoutreix,Bruno O. Villoutreix +4 more
TL;DR: This work reports on the investigation of a pool of interpretable molecular descriptors for solvent-exposed and buried co-crystallized ligands, finding several descriptors found to be significantly different between the two classes and were further exploited using machine-learning approaches.
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.