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Joe Eyermann received his B. S. in Chemistry from Marietta College in 1977 and a PhD in Inorganic Chemistry from Miami University of Ohio in 1981. Following postdoctoral studies at UC Berkeley he joined the DuPont Company where he began his career in applying computational methods to drug discovery. His early work at DuPont involving application of 3D database searching strategies helped lead to the structure-based design of the cyclic urea series of HIV protease inhibitors. More recently, while at AstraZeneca, he has continued his work in anti-infectives by applying structure-based and pharmacophore methods to the identification and optimization of HTS and fragment leads.
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Using Homology Models and Structure-Based Design to Improve the MAO-A Safety Profile of Oxazolidinone Antibacterials
C. Eyermann, P. Fleming, M. Gravestock, G. Kern, F. Reck, and F. Zhou, Infection Discovery, Cancer and Infection Research Area, AstraZeneca, R&D Boston Inc, 35 Gatehouse Drive, Waltham, MA 02451, USA and T. Jones and R. Ramsay, University of St. Andrews, North Haugh, St. Andrews, Fife KY16 9ST, UK
Oxazolidinones are a new class of synthetic antibacterial agents that show good activity against Gram-positive bacteria. A concern with oxazolidinones as a drug class has been inhibition of MAO, especially Type A (MAO-A), due to structural similarity to MAO inhibitors like toloxatone. Inhibition of MAO-A could potentially lead to severe hypertensive crises as a result of ingestion of tyramine-containing food together with an oxazolidinone drug. It is therefore desirable to develop novel oxazolidinone drugs, which have improved activity against linezolid-resistant Gram-positive bacteria and show an improved safety profile with regard to MAO-A inhibition. Using the published crystal structure of MAO-B, a homology model of MAO-A has been built and used to interpret experimental studies on the orientation of oxazolidinones in the MAO-A active site. In addition, the homology model has been used to guide the design of new oxazolidinones which have reduced MAO-A inhibition while maintaining good anitbacterial activity.
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