Frederick, MD, United States
Frederick, MD, United States

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Peach M.L.,CADD Group | Zakharov A.V.,U.S. National Cancer Institute | Liu R.,U.S. Army | Pugliese A.,U.S. National Cancer Institute | And 4 more authors.
Future Medicinal Chemistry | Year: 2012

Metabolism has been identified as a defining factor in drug development success or failure because of its impact on many aspects of drug pharmacology, including bioavailability, half-life and toxicity. In this article, we provide an outline and descriptions of the resources for metabolism-related property predictions that are currently either freely or commercially available to the public. These resources include databases with data on, and software for prediction of, several end points: metabolite formation, sites of metabolic transformation, binding to metabolizing enzymes and metabolic stability. We attempt to place each tool in historical context and describe, wherever possible, the data it was based on. For predictions of interactions with metabolizing enzymes, we show a typical set of results for a small test set of compounds. Our aim is to give a clear overview of the areas and aspects of metabolism prediction in which the currently available resources are useful and accurate, and the areas in which they are inadequate or missing entirely. © 2012 Future Science Ltd.


Zakharov A.V.,U.S. National Cancer Institute | Peach M.L.,CADD Group | Sitzmann M.,U.S. National Cancer Institute | Filippov I.V.,CADD Group | And 6 more authors.
Future Medicinal Chemistry | Year: 2012

Background: The most important factor affecting metabolic excretion of compounds from the body is their half-life time. This provides an indication of compound stability of, for example, drug molecules. We report on our efforts to develop QSAR models for metabolic stability of compounds, based on in vitro half-life assay data measured in human liver microsomes. Method: A variety of QSAR models generated using different statistical methods and descriptor sets implemented in both open-source and commercial programs (KNIME, GUSAR and StarDrop) were analyzed. The models obtained were compared using four different external validation sets from public and commercial data sources, including two smaller sets of in vivo half-life data in humans. Conclusion: In many cases, the accuracy of prediction achieved on one external test set did not correspond to the results achieved with another test set. The most predictive models were used for predicting the metabolic stability of compounds from the open NCI database, the results of which are publicly available on the NCI/CADD Group web server (http://cactus.nci.nih.gov). © 2012 Future Science Ltd.


Combettes L.E.,University of Oxford | Clausen-Thue P.,University of Oxford | King M.A.,CADD Group | Odell B.,University of Oxford | And 3 more authors.
Chemistry - A European Journal | Year: 2012

A series of 3-fluoropyrrolidines have been studied to investigate the influence of the stereoelectronic fluorine gauche effect on ring conformations in the solid state by single-crystal X-ray analysis and in solution phase by NMR spectroscopy. As part of these studies 1D 19F-1H heteronuclear NOE (HOESY) experiments have been optimised for applications to small molecules and are described in detail. These have been employed to estimate 19F-1H internuclear distances and were combined with vicinal 3J(F,H) and 3J(H,H) scalar coupling constants to analyse the ring conformations. Where possible the derived solution-phase structural data have been compared with those of the crystalline state. The results demonstrate the influence of the gauche effect in stabilising C γ-exo conformations of the fluorinated pyrrolidines. It was further shown that when steric interactions were also present, this conformational bias was diminished and the contribution of the alternative Cγ-endo conformation was seen to increase in solution at lower sample temperatures. HOESY does it! 1D 19F-1H heteronuclear NOE experiments have been optimised for the study of small molecules and applied to investigate the conformations of fluorinated pyrrolidines in solution and the stabilising influence of the stereoelectronic fluorine gauche effect (see figure). Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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