Interface of Evolution and Structure Based Drug Design

Our Lab

Schiffer LabConstraining evolution and avoiding drug resistance

Drug resistance occurs when, through evolution, a disease no longer responds to medications. Resistance impacts the lives of millions, limiting the effectiveness of many of our most potent drugs. This often happens under the selective pressure of therapy in bacterial, viral and fungal infections and cancer due to their rapid evolution.

We combine a variety of experimental and computational techniques to understand the molecular basis of drug resistance. Our new paradigm of drug design minimizes chances of resistance. Realizing that disrupting the drug target’s activity is necessary but not sufficient for developing a robust drug that avoids resistance.

                                                                         Meet the Lab

  

Research Focus

Strategies and Systems

We use multidisciplinary approaches, combining crystallography, enzymology, molecular dynamics and organic chemistry, to elucidate the molecular mechanisms of drug resistance. Resistance occurs when a heterogeneous populations of a drug target is challenged by the selective pressure of a drug. In cancer and viruses this heterogeneity is partially caused APOBEC3’s. We discovered resistance mutations occur either where drugs physically contact regions of the drug target that are not essential for substrate recognition or alter the ensemble dynamics of the drug target favoring substrate. We leverage these insights into a new strategies in structure-based drug design to minimize the likelihood for resistance by designing inhibitors to stay within the substrate envelope. This strategy not only describes most of the primary drug resistance for HIV, Hepatitis C viral protease inhibitors and influenza neuraminidase, but is generally applicable in the development of novel drugs that are less susceptible to resistance.  

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Publications

Kobertz Publications

Molecular Basis for Differential Patterns of Drug Resistance in Influenza N1 and N2 Neuraminidase

December 13, 2016
Author(s): Kristina L. Prachanronarong, Aysegul Ozen, Kelly Thayer, L. Safak Yilmaz, Konstantin B. Zeldovich, Daniel N. Bolon, Timothy F. Kowalik, Jeffrey D. Jensen, Robert W. Finberg, Jennifer P. Wang, Nese Kur...

 

 

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Contact Us

Office:
Lazare Research Building 828
Campus Map (pdf)

Phone:
508-856-8008 (office)

Email:
Celia.Schiffer@umassmed.edu

Mailing Address:
University of Massachusetts Medical School
Attn: Dr. Celia Schiffer/BMP department
364 Plantation St LRB828
Worcester, MA 01605

Join Us

We are always interested in applications from qualified candidates at postdoctoral and research associate levels.

Read more here

Undergraduates interested in pursuing a PhD at UMass Medical School should apply directly to the Graduate School of Biomedical Sciences Program.

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