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
TLDR
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.Abstract:
Oral bioavailability measurements in rats for over 1100 drug candidates studied at SmithKline Beecham Pharmaceuticals (now GlaxoSmithKline) have allowed us to analyze the relative importance of molecular properties considered to influence that drug property. Reduced molecular flexibility, as measured by the number of rotatable bonds, and low polar surface area or total hydrogen bond count (sum of donors and acceptors) are found to be important predictors of good oral bioavailability, independent of molecular weight. That on average both the number of rotatable bonds and polar surface area or hydrogen bond count tend to increase with molecular weight may in part explain the success of the molecular weight parameter in predicting oral bioavailability. The commonly applied molecular weight cutoff at 500 does not itself significantly separate compounds with poor oral bioavailability from those with acceptable values in this extensive data set. Our observations suggest that compounds which meet only the two cr...read more
Citations
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SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules
TL;DR: The new SwissADME web tool is presented that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar are presented.
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.
Journal ArticleDOI
The combinatorial synthesis of bicyclic privileged structures or privileged substructures
TL;DR: Privileged substructures are believed to achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns.
Journal ArticleDOI
Improved protein-ligand docking using GOLD.
Marcel L. Verdonk,Jason C. Cole,Michael J. Hartshorn,Christopher W. Murray,Richard D. Taylor +4 more
TL;DR: In terms of producing binding energy estimates, the Goldscore function appears to perform better than the Chemscore function and the two consensus protocols, particularly for faster search settings.
Journal ArticleDOI
Escape from flatland: increasing saturation as an approach to improving clinical success.
TL;DR: It is demonstrated that saturation correlates with solubility, an experimental physical property important to success in the drug discovery setting, and both complexity and the presence of chiral centers correlate with success as compounds transition from discovery, through clinical testing, to drugs.
References
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Journal ArticleDOI
Goodman and Gilman's the Pharmacological Basis of Therapeutics
William H. Stigelman,Pharm D. +1 more
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Drug-like properties and the causes of poor solubility and poor permeability
TL;DR: There are currently about 10000 drug-like compounds, and true diversity does not exist in experimental combinatorial chemistry screening libraries because current ADME experimental screens are multi-mechanisms, and predictions get worse as more data accumulates.
Journal ArticleDOI
Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of Drug transport properties
TL;DR: The method, termed topological PSA (TPSA), provides results which are practically identical with the 3D PSA, while the computation speed is 2-3 orders of magnitude faster and may be used for fast bioavailability screening of virtual libraries having millions of molecules.