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Interface of Evolution and Structure Based Drug Design

Our Lab

Constraining evolution and avoiding drug resistance

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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.

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Research Focus

Strategies and Systems

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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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In The News  

Publications

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Total: 1 results
  • Optimizing the refinement of merohedrally twinned P61 HIV-1 protease-inhibitor cocrystal structures.

    Icon for International Union of Crystallography Related Articles

    Optimizing the refinement of merohedrally twinned P61 HIV-1 protease-inhibitor cocrystal structures.

    Acta Crystallogr D Struct Biol. 2020 Mar 01;76(Pt 3):302-310

    Authors: Lockbaum GJ, Leidner F, Royer WE, Kurt Yilmaz N, Schiffer CA

    Abstract
    Twinning is a crystal-growth anomaly in which protein monomers exist in different orientations but are related in a specific way, causing diffraction reflections to overlap. Twinning imposes additional symmetry on the data, often leading to the assignment of a higher symmetry space group. Specifically, in merohedral twinning, reflections from each monomer overlap and require a twin law to model unique structural data from overlapping reflections. Neglecting twinning in the crystallographic analysis of quasi-rotationally symmetric homo-oligomeric protein structures can mask the degree of structural non-identity between monomers. In particular, any deviations from perfect symmetry will be lost if higher than appropriate symmetry is applied during crystallographic analysis. Such cases warrant choosing between the highest symmetry space group possible or determining whether the monomers have distinguishable structural asymmetries and thus require a lower symmetry space group and a twin law. Using hexagonal cocrystals of HIV-1 protease, a C2-symmetric homodimer whose symmetry is broken by bound ligand, it is shown that both assigning a lower symmetry space group and applying a twin law during refinement are critical to achieving a structural model that more accurately fits the electron density. By re-analyzing three recently published HIV-1 protease structures, improvements in nearly every crystallographic metric are demonstrated. Most importantly, a procedure is demonstrated where the inhibitor can be reliably modeled in a single orientation. This protocol may be applicable to many other homo-oligomers in the PDB.

    PMID: 32133994 [PubMed - indexed for MEDLINE]

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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.

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