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Do enzyme-inhibiting drugs show increased reliance

This research proposal by Dan Nacu explores the significance of certain chemical properties in enzyme-inhibiting drug binding. By using simulation models and analyzing factors like hydrophobicity and electrostatics, the study aims to uncover key properties affecting binding. The experiment involves analyzing 46 enzyme-inhibitor complexes and generating 920 simulated structures to identify important chemical properties for binding. By weighing variables in the HINT equation, the study seeks to find the most crucial property for enzyme-inhibitor complexes. The methodology includes L_RMSD testing and scoring methods to determine the best matches. Future directions may include exploring different models and complexes.

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Do enzyme-inhibiting drugs show increased reliance

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  1. Do enzyme-inhibiting drugs show increased reliance on certain chemical properties for binding to their respective enzymes?

  2. Chemical properties that affect binding of enzyme-inhibiting drugs to enzymes Research proposal by Dan Nacu

  3. Why is this significant? Drug Development • Computers

  4. How can it be done? • Simulation Models • Shape Complementarity • Chemical Properties

  5. How can it be done? • Chemical Properties • Solvent Accessible Surface Area • Hydrophobicity • Electrostatics • Van Der Waal’s Forces • Residue Pair potential • Desolvation Energies • Atomic Contact Energies • Complementary Determining Regions • etc… • A lot of options…

  6. Its been done before…in a different way. • Li et al, 2007 • Their Equation • Their Results

  7. How will this be different? • Introducing HINT • Hydropathic INTeractions • The HINT Equation

  8. What can be done? • By weighing each variable in HINT, the most important chemical property for enzyme/inhibitor complexes can be found. Do enzyme-inhibiting drugs show increased reliance on certain chemical properties for binding to their respective enzymes? • Remember The Question

  9. What’s the experiment? • Start with 46 enzyme inhibitor complexes • from the Benchmark 5.

  10. What’s the experiment? • Bound • Unbound • FTDock • Huge list of possible complexes

  11. What’s the experiment? • Huge list of possible complexes • L_RMSD Testing • Ligand_Root-Mean-Square-Deviation • Top 20 Structures

  12. What’s the experiment? • Top 20 Structures • For 46 complexes = • 920 simulated structures. • For both bound and unbound, 1,840 total • Lets look at just one

  13. What’s the experiment?

  14. What’s the experiment? • In the end… • 23,000 HINT Scores for Bound • 23,000 HINT Scores for Unbound • 46,000 scores • 46•20•5•5 = 23,000

  15. What’s the experiment? • Highest 50 HINT Scores for each complex • L_RMSD Testing • Ligand_Root-Mean-Square-Deviation • Find best match for each complex • Results!

  16. Possible Results

  17. Possible Results

  18. In the future… • Different models (besides HINT) • Different complexes (besides enzyme/inhibitor)

  19. Questions?

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