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| About Georgia McGaughey (Merck) |
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Georgia McGaughey obtained her Ph.D. in physical chemistry from the University of Georgia where she parameterized positively nitrogen-containing atoms for the MM2 and MM3 suite of software. She also focused on small molecule inhibitors of QSAR studies of choline acetyltransferase inhibitors, an enzyme involved in the neurodegenerative disorder, Alzheimer's Disease. She then carried out her post-doctoral work under the guidance of Professor Tony Rappé at Colorado State University where she studied pi-stacking arrangements as manifested in the Protein Data Bank. In 1997 she joined Wyeth Laboratories as a computational chemist designing inhibitors which target the dopamine and 5HT GPCRs. Since 1999 she has been a member of the Molecular Systems group at Merck Research Laboratories and has published in the areas of virtual screening, BACE-1, gp41 and KDR.
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Design of Beta-secretase (BACE-1) inhibitors through in silico property-based fragment scanning
Georgia B. McGaughey (1), J. Christopher Culberson (1), Bradley P. Feuston (1), Simon K. Kearsley (2), Ralph Mosley (2) and M. Katharine Holloway (1)Merck Research Laboratories
(1) Molecular Systems Department, P.O. BOX 4, West Point, PA 19486
(2) Molecular Systems Department, P.O. BOX 2000, Rahway, NJ 07065
Beta-Secretase (BACE-1) is a transmembrane aspartyl protease intimately involved in the neurodegenerative disorder, Alzheimer’s disease. With a significant amount of in-house structural knowledge of BACE-1, chemotype-specific scoring functions for rank-ordering virtual compounds have proven useful for explaining structure activity relationships. In advance of rank-ordering virtual compounds, scoring functions were evaluated for a series of tertiary carbinamine inhibitors to obtain a correlation with the experimentally determined Ki values. These inhibitors were examined in crystallographic complexes with BACE-1 which revealed 10s loop motion in the S3 pocket. Combining these scoring functions with Merck’s unique virtual compound library tools provided an opportunity for focused library designs which directly impact lead finding/optimization in a timely manner. To facilitate the design and optimization of virtual BACE-1 compound libraries, Merck’s Virtual Library ToolKit (VLTK) has been enhanced to include 3D library construction. This presentation will focus on the various aspects of focused library designs and specifically, the application to BACE-1 inhibitors.
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