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
More filters
Journal ArticleDOI
Trends and exceptions of physical properties on antibacterial activity for Gram-positive and Gram-negative pathogens.
TL;DR: Physical properties of antibacterial project compounds with whole cell activity against Gram-negative or Gram-positive pathogens were profiled and compared to actives found from high throughput screens conducted on both biochemical and phenotypic bacterial targets and illustrated that compounds least susceptible to efflux were those which were highly polar and small in MW or very large and typically zwitterionic.
Journal ArticleDOI
Self-Assembled Tat Nanofibers as Effective Drug Carrier and Transporter
TL;DR: Fluorescence and confocal microscopy imaging show that the Tat nanofibers can effectively transport encapsulated molecules into the cells through an adsorptive-mediated endocytosis pathway, and Cytotoxicity experiments and flow cytometry measurements demonstrate that PTX loaded in the nan ofibers exerts its cytotoxicity against cancer cells by arresting the cells at the G2/M phase, the same working mechanism as free PTX.
Journal ArticleDOI
Cell permeability beyond the rule of 5
TL;DR: Current knowledge of compound properties that govern transporter effects of bRo5 drugs is limited and requires further fundamental and comprehensive studies, so developments in computational conformational analysis will aid design of such compounds and hence prediction of cell permeability.
Journal ArticleDOI
Therapeutic target database update 2022: facilitating drug discovery with enriched comparative data of targeted agents.
Ying Zhou,Yintao Zhang,Xichen Lian,Fengcheng Li,Chaoxin Wang,Feng Zhu,Yunqing Qiu,Yu Zong Chen,Yu Zong Chen +8 more
TL;DR: In this article, a major update of the Therapeutic Target Database, previously featured in NAR, was introduced, which includes poor binders and non-binders for developing discovery tools, prodrugs for improved therapeutics, co-targets of therapeutic targets for multi-target strategies and off-target investigations, and collective structureactivity and drug-likeness landscapes of enhanced drug feature.
Journal ArticleDOI
Toward performance-diverse small-molecule libraries for cell-based phenotypic screening using multiplexed high-dimensional profiling
Mathias Wawer,Kejie Li,Sigrun M. Gustafsdottir,Vebjorn Ljosa,Nicole E. Bodycombe,Melissa A. Marton,Katherine L Sokolnicki,Mark-Anthony Bray,Melissa M. Kemp,Ellen Winchester,Bradley K. Taylor,George B. Grant,C. Suk-Yee Hon,Jeremy R. Duvall,J. Anthony Wilson,Joshua A. Bittker,Vlado Dančík,Rajiv Narayan,Aravind Subramanian,Wendy Winckler,Todd R. Golub,Anne E. Carpenter,Alykhan F. Shamji,Stuart L. Schreiber,Paul A. Clemons +24 more
TL;DR: This study explores a cost-effective way of rapidly assessing the biological performance diversity of a screening collection in a single assay by simultaneously measuring a large number of cellular features, unbiased profiling assays can distinguish compound effects with high resolution and thus measure performance diversity.
References
More filters
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.