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Article
Interdependence of Inhibitor Recognition in HIV-1 Protease
University of Massachusetts Medical School Faculty Publications
  • Janet L. Paulsen, University of Massachusetts Medical School
  • Florian Leidner, University of Massachusetts Medical School
  • Debra A. Ragland, University of Massachusetts Medical School
  • Nese Kurt Yilmaz, University of Massachusetts Medical School
  • Celia A. Schiffer, University of Massachusetts Medical School
UMMS Affiliation
Department of Biochemistry and Molecular Pharmacology; Schiffer Lab
Publication Date
5-9-2017
Document Type
Article
Abstract
Molecular recognition is a highly interdependent process. Subsite couplings within the active site of proteases are most often revealed through conditional amino acid preferences in substrate recognition. However, the potential effect of these couplings on inhibition and thus inhibitor design is largely unexplored. The present study examines the interdependency of subsites in HIV-1 protease using a focused library of protease inhibitors, to aid in future inhibitor design. Previously a series of darunavir (DRV) analogs was designed to systematically probe the S1' and S2' subsites. Co-crystal structures of these analogs with HIV-1 protease provide the ideal opportunity to probe subsite interdependency. All-atom molecular dynamics simulations starting from these structures were performed and systematically analyzed in terms of atomic fluctuations, intermolecular interactions, and water structure. These analyses reveal that the S1' subsite highly influences other subsites: the extension of the hydrophobic P1' moiety results in 1) reduced van der Waals contacts in the P2' subsite, 2) more variability in the hydrogen bond frequencies with catalytic residues and the flap water, and 3) changes in the occupancy of conserved water sites both proximal and distal to the active site. In addition, one of the monomers in this homodimeric enzyme has atomic fluctuations more highly correlated with DRV than the other monomer. These relationships intricately link the HIV-1 protease subsites and are critical to understanding molecular recognition and inhibitor binding. More broadly, the interdependency of subsite recognition within an active site requires consideration in the selection of chemical moieties in drug design; this strategy is in contrast to what is traditionally done with independent optimization of chemical moieties of an inhibitor.
Keywords
  • HIV-1 protease,
  • protease inhibitors,
  • drug resistance,
  • drug design
Rights and Permissions
This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
DOI of Published Version
10.1021/acs.jctc.6b01262
Source
J Chem Theory Comput. 2017 May 9;13(5):2300-2309 Epub 2017 Apr 11. Link to article on publisher's site
Related Resources

Link to Article in PubMed

PubMed ID
28358514
Citation Information
Janet L. Paulsen, Florian Leidner, Debra A. Ragland, Nese Kurt Yilmaz, et al.. "Interdependence of Inhibitor Recognition in HIV-1 Protease" Vol. 13 Iss. 5 (2017) ISSN: 1549-9618 (Linking)
Available at: http://0-works.bepress.com.library.simmons.edu/celia_schiffer/136/