HOME- Bryn Mawr Conference
- Workshops & Training
- 2010 Oxford (Discovery)
- 2010 Oxford (ADMET)
- 2009 Oxford (Discovery)
- 2009 Oxford (ADMET)
- Bassan, A
- Cronin, M
- Hardy, B
- Helma, C
- Hopfinger, T
- Judson, P
- Leahy, D
- Madden, J
- Michielan, L
- Narayanan, D
- Myatt, G
- Obrezanova, O
- Thomas, S
- Zamora, I
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Anton [Tony] Hopfinger is currently Distinguished Research Professor of Pharmacy at the University of New Mexico, Professor Emeritus of Medicinal Chemistry at the University of Illinois and Founder and Chief Science Officer of The Chem21 Group, Incorporated. He is also the former Director of Medicinal Chemistry at G.D. Searle & Company [now part of Pfizer Pharmaceuticals], and has held the position of Professor of Macromolecular Science at Case Western Reserve University. His field of interest is computer-assisted molecular discovery, CAMD, with a current special interest in predictive ADME and toxicology. He has published over 270 research papers, including three books, has presented over 400 invited lectures throughout the world on CAMD and is a coauthor on ten patents. Dr. Hopfinger has also been active as an entrepreneur being the cofounder of five companies, and serving on the boards of seven other start-up companies. He is, or has been, a consultant to more than 45 biotechnology, chemical and pharmaceutical companies.
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Modelling Skin Penetration, Irritation, Sensitization and Penetration Enhancement
Tony Hopfinger (University of New Mexico)
The modeling of an ADMET endpoint is highly dependent upon the complexity of the molecular mechanism involved. In cases where the molecular mechanism is complex, and/or pharmacological understanding is quite limited, an empirical informatics approach to develop predictive models is the preferred methodology to apply. Unfortunately, for ADMET studies, few high-level 3D and 4D level descriptors are available to model complex mechanisms of action as compared to drug potency QSAR investigations. We have developed a set of universal descriptors, called 4D-fingerprints, 4D-FP, which capture the three-dimensional size, shape, chemical composition, reactive state and molecular flexibility of a molecule for informatics type ADMET modeling. For ADMET endpoints where cellular membrane permeation and diffusion are involved, a pseudo structure-based design approach called membrane-interaction (MI-) QSAR analysis can be applied. Here descriptors derived from the simulation of an organic molecule passing through a phospholipid membrane assembly are used with intramolecular descriptors derived from the organic molecule to build MI-QSAR models. With our most recently developed MI-QSAR descriptor, the difference in the integrated cylindrical distribution functions over a phospholipid monolayer model, in and out of the presence of a monolayer penetrator, greatly reduces the size and complexity of the MI-QSAR models as compared to corresponding classic intramolecular QSAR models. In this workshop participants will study "Skin" ADMET endpoint modeling, using both 4D-FP and/or MI-QSAR descriptors in tandem with the more 'traditional' 1D and 2D intramolecular descriptors. The specific skin ADMET endpoint 4D-FP and MI-QSAR case study applications will be:
a) skin penetration - which is desired for transdermal delivery, but may involve unwanted irritation and sensitization
b) skin irritation and sensitization - requires study of both transport and chemical reactivity
c) skin penetration enhancement - a desired property for cosmetics and drugs, but may involve toxicity issues
d) therapeutic index modeling - optimizing penetration and minimizing irritation, sensitization and/or toxicity as a function of chemical structure
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