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Albany 2019: 20th Conversation - Abstracts

category image Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

Constraining Evolution — Avoiding Drug Resistance: Lessons from Viruses

Drug resistance negatively impacts the lives of millions of patients and costs our society billions of dollars by limiting the longevity of many of our most potent drugs. Drug resistance can be caused by a change in the balance of molecular recognition events that selectively weakens inhibitor binding but maintains the biological function of the target. To reduce the likelihood of drug resistance, a detailed understanding of the target’s function is necessary.

Both structure at atomic resolution and evolutionarily constraints on its variation is required. This rationale was derived from our lab’s experience with substrate recognition and drug resistance in HIV, HCV and Influenza. In particular we have acquired a rich and versatile experimental dataset of viral proteases altered by the selective pressures of inhibitors. With this data we are integrating alterations in both the protein sequence and the inhibitor with changes in potency and we correlate this data to our co-crystal structures and our strategy of parallel molecular dynamics(pMD) to elucidate molecular mechanisms of drug resistance.

pMD is a strategy we have developed to collectively analyze a series of MD simulations of similar yet distinct molecular complexes to decipher conformational and dynamic differences responsible for changes in molecular recognition. We perform pMD simulations on complexes with varying protein sequence and ligand identity to unravel structural and dynamic properties that underlie coupled changes in molecular recognition and resistance. We have applied this pMD strategy to protein-ligand complexes for series of natural substrates, inhibitors, and protease mutations. Combined with experimental potency data, we determine which physical properties or molecular interactions, including with water, are key to molecular recognition for a given system.

These changes in structure and dynamics dictate the interdependency of molecular mechanism of resistance and are principals that are generally applicable to other quickly evolving diseases where drug resistance is quickly evolving.

References

    1. Molecular Mechanism of Resistance in a Clinically Significant Double-Mutant Variant of HCV NS3/4A Protease. Matthew AN, Leidner F, Newton A, Petropoulos CJ, Huang W, Ali A, KurtYilmaz N, Schiffer CA. Structure. 2018 Oct 2;26(10):1360-1372.e5. doi: 10.1016/j.str.2018.07.004. Epub 2018 Aug 23.

    2. Hydration Structure and Dynamics of Inhibitor-Bound HIV-1 Protease. Leidner F, Kurt Yilmaz N, Paulsen J, Muller YA, Schiffer CA. J Chem Theory Comput. 2018 May 8;14(5):2784-2796. doi: 10.1021/acs.jctc.8b00097. Epub 2018 Apr 18.

    3. Interdependence of Inhibitor Recognition in HIV-1 Protease. Paulsen JL, Leidner F, Ragland DA, Kurt Yilmaz N, Schiffer CA. J Chem Theory Comput. 2017 May 9;13(5):2300-2309. doi: 10.1021/acs.jctc.6b01262. Epub 2017 Apr 11.

    4. Molecular and Dynamic Mechanism Underlying Drug Resistance in Genotype 3 Hepatitis C NS3/4A Protease. Soumana DI, Kurt Yilmaz N, Ali A, Prachanronarong KL, Schiffer CA. J Am Chem Soc. 2016 Sep 14;138(36):11850-9. doi: 10.1021/jacs.6b06454. Epub 2016 Sep 2.

    5. Molecular Basis for Differential Patterns of Drug Resistance in Influenza N1 and N2 Neuraminidase. Prachanronarong KL, Özen A, Thayer KM, Yilmaz LS, Zeldovich KB, Bolon DN, Kowalik TF, Jensen JD, Finberg RW, Wang JP, Kurt-Yilmaz N, Schiffer CA. J Chem Theory Comput. 2016 Dec 13;12(12):6098-6108. Epub 2016 Nov 17.

    6. Drug resistance conferred by mutations outside the active site through alterations in the dynamic and structural ensemble of HIV-1 protease. Ragland DA, Nalivaika EA, Nalam MN, Prachanronarong KL, Cao H, Bandaranayake RM, Cai Y, Kurt-Yilmaz N, Schiffer CA. J Am Chem Soc. 2014 Aug 27;136(34):11956-63. doi: 10.1021/ja504096m. Epub 2014 Aug 18.

    7. Structural basis and distal effects of Gag substrate coevolution in drug resistance to HIV-1 protease. Özen A, Lin KH, Kurt Yilmaz N, Schiffer CA. Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):15993-8. doi: 10.1073/pnas.1414063111. Epub 2014 Oct 29.

Celia Schiffer

Biochemistry and Molecular Pharmacology
Director Institute for Drug Resistance
University of Massachusetts Medical School
Worcester MA, 01605-2324

Celia.Schiffer@umassmed.edu