Structure based analyses of HIV PI-resistance

Poster number: 15

M. Becker(1), M. Beig(1), P. Braun(5), M. Däumer(3), F. Dill(1), N. Dybowski(1), N. Enkler(1), M. Erlekamm(1), M. Gilsdorf(1), O. Grober(1), T. Harder(1), D. Hoffmann(1,4), G. Humpert(1), R. Kaiser(3), T. Koch(1), K. Korn(2), J. Krüger(1), J. Kunert(1), E. Meurer(1), C. Pfleger(1), M. Prinz(1), T. Schmidt(1), Y. Schuh(1), M. Wagner(1), H. Walter(2), S. Wieland(1), T. Zuhl(1)

  1. (1) Bingen University of Applied Sciences, Bioinformatics Project Group, Berlinstr. 109, D-55411 Bingen am Rhein
  2. (2) University of Erlangen-Nürnberg, Institute of Clinical and Molecular Virology, German National Reference Center for Retroviruses, Schlossgarten 4, D-91054 Erlangen
  3. (3) University of Cologne, Institute of Virology, Fürst-Pückler-Str. 56, D-50935 Cologne
  4. (4) Centre of Advanced European Studies and Research, Research Group Functional Peptides, Ludwig-Erhard-Allee 2, D-53175 Bonn
  5. (5) PZB, Blondelstr. 9, D-52062 Aachen

Mutation L76V of HIV-PR confers resistance against APV and LPV, and at the same time re-establishes sensitivity to SQV and ATZ. Here, we explore various aspects of this mutation using a range of bioinformatics methods. Amongst these aspects are (A) a consensus 3D-structure prediction of the free enzyme; (B) models of complexes of the mutant with various drugs, that e.g. in case of LPV suggest a molecular resistance mechanism as a specific hydrophobic contact of LPV with L76 is lost; (C) estimates of the changed affinities of the drugs to the protease from structure based simulations and calculations; (D) proposals for changes in the drug molecules to re-instate susceptibility; (E) prediction of possible changes in HIV-PR likely to produce similar effects as L76V.