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Towards understanding molecular mechanism of drug resistance: L76V Daniel.Hoffmann@uni-due.de 2007 c 1 HIV PR complexed with drug (LPV) Daniel.Hoffmann@uni-due.de 2007 c 2 Molecular location of L76V Daniel.Hoffmann@uni-due.de

  1. Towards understanding molecular mechanism of drug resistance: L76V � Daniel.Hoffmann@uni-due.de 2007 c 1

  2. HIV PR complexed with drug (LPV) � Daniel.Hoffmann@uni-due.de 2007 c 2

  3. Molecular location of L76V � Daniel.Hoffmann@uni-due.de 2007 c 3

  4. Molecular location of L76V � Daniel.Hoffmann@uni-due.de 2007 c 4

  5. Molecular location of L76V � Daniel.Hoffmann@uni-due.de 2007 c 5

  6. Possible effects of L76V No direct interaction of L76V with drugs ⇒ � Daniel.Hoffmann@uni-due.de 2007 c 6

  7. Possible effects of L76V No direct interaction of L76V with drugs ⇒ possible effects somehow “long range”: � Daniel.Hoffmann@uni-due.de 2007 c 6

  8. Possible effects of L76V No direct interaction of L76V with drugs ⇒ possible effects somehow “long range”: ◮ electrostatics � Daniel.Hoffmann@uni-due.de 2007 c 6

  9. Possible effects of L76V No direct interaction of L76V with drugs ⇒ possible effects somehow “long range”: ◮ electrostatics ◮ conformational rearrangements ⇒ � Daniel.Hoffmann@uni-due.de 2007 c 6

  10. Possible effects of L76V No direct interaction of L76V with drugs ⇒ possible effects somehow “long range”: ◮ electrostatics ◮ conformational rearrangements ⇒ indirect effects � Daniel.Hoffmann@uni-due.de 2007 c 6

  11. L76V–drug interactions: LPV "WT" � Daniel.Hoffmann@uni-due.de 2007 c 7

  12. L76V–drug interactions: LPV (II) diff. L76V − "WT" � Daniel.Hoffmann@uni-due.de 2007 c 8

  13. L76V–drug interactions: APV "WT" � Daniel.Hoffmann@uni-due.de 2007 c 9

  14. L76V–drug interactions: APV (II) L76V � Daniel.Hoffmann@uni-due.de 2007 c 10

  15. L76V–drug interactions: SQV "WT" � Daniel.Hoffmann@uni-due.de 2007 c 11

  16. L76V–drug interactions: SQV (II) diff. L76V− "WT" � Daniel.Hoffmann@uni-due.de 2007 c 12

  17. Model based estimates of resistance Estimate of ∆∆ G ( WT · drug → L 76 V · drug ) based on molecular model: � Daniel.Hoffmann@uni-due.de 2007 c 13

  18. Model based estimates of resistance Estimate of ∆∆ G ( WT · drug → L 76 V · drug ) based on molecular model: estimate of ∆∆ G drug phenotype APV 14.5 resistant LPV 7.8 resistant SQV 9.0 susceptible � Daniel.Hoffmann@uni-due.de 2007 c 13

  19. Reasons for discrepancy � Daniel.Hoffmann@uni-due.de 2007 c 14

  20. Reasons for discrepancy: global rearrangements 35 WT binding pocket 30 25 All % RF>10 20 15 10 5 0 APV LPV SQV � Daniel.Hoffmann@uni-due.de 2007 c 15

  21. Next steps ◮ More complex model, � Daniel.Hoffmann@uni-due.de 2007 c 16

  22. Next steps ◮ More complex model, that is also more compute intensitive � Daniel.Hoffmann@uni-due.de 2007 c 16

  23. Next steps ◮ More complex model, that is also more compute intensitive ◮ Test with comprehensive dataset � Daniel.Hoffmann@uni-due.de 2007 c 16

  24. Next steps ◮ More complex model, that is also more compute intensitive ◮ Test with comprehensive dataset ◮ Use as predictive tool � Daniel.Hoffmann@uni-due.de 2007 c 16

  25. Acknowledgments The whole AREVIR team: ◮ Patrick Braun, Martin Däumer, Rolf Kaiser, Klaus Korn, Hauke Walter, ... � Daniel.Hoffmann@uni-due.de 2007 c 17

  26. Acknowledgments The whole AREVIR team: ◮ Patrick Braun, Martin Däumer, Rolf Kaiser, Klaus Korn, Hauke Walter, ... and: ◮ Yvonne Schuh ◮ Karen Willbrand � Daniel.Hoffmann@uni-due.de 2007 c 17

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