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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Publications

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Total: 1 results
  • Structural Adaptation of Darunavir Analogs Against Primary Mutations in HIV-1 Protease.

    Author(s): Lockbaum GJ, Leidner F, Rusere LN, Henes M, Kosovrasti K, Nachum GS, Nalivaika EA, Ali A, Kurt Yilmaz N, Schiffer CA
    Related Articles

    Structural Adaptation of Darunavir Analogs Against Primary Mutations in HIV-1 Protease.

    ACS Infect Dis. 2018 Dec 13;:

    Authors: Lockbaum GJ, Leidner F, Rusere LN, Henes M, Kosovrasti K, Nachum GS, Nalivaika EA, Ali A, Kurt Yilmaz N, Schiffer CA

    Abstract
    HIV-1 protease is one of the prime targets of agents used in antiretroviral therapy against HIV. However, under selective pressure of protease inhibitors, primary mutations at the active site weaken inhibitor binding to confer resistance. Darunavir (DRV) is the most potent HIV-1 protease inhibitor in clinic; resistance is limited, as DRV fits well within the substrate envelope. Nevertheless, resistance is observed due to hydrophobic changes at residues including I50, V82 and I84 that line the S1/S1' pocket within the active site. Through enzyme inhibition assays and a series of 12 crystal structures, we interrogated susceptibility of DRV and two potent analogs to primary S1' mutations. The analogs had modifications at the hydrophobic P1' moiety compared to DRV to better occupy the unexploited space in the S1' pocket where the primary mutations were located. Considerable losses of potency were observed against protease variants with I84V and I50V mutations for all three inhibitors. The crystal structures revealed an unexpected conformational change in the flap region of I50V protease bound to the analog with the largest P1' moiety, indicating interdependency between the S1' subsite and the flap region. Collective analysis of protease-inhibitor interactions in the crystal structures using principle component analysis was able to distinguish inhibitor identity and relative potency solely based on vdW contacts. Our results reveal the complexity of the interplay between inhibitor P1' moiety and S1' mutations, and validate principle component analyses as a useful tool for distinguishing resistance and inhibitor potency.

    PMID: 30543749 [PubMed - as supplied by publisher]

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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

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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.