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The physics of computational drug discovery


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This is a short lecture that I gave to school childrenin June 2012, at University College Dublin, Ireland about the amazing "Physics of Drug Discovery." It can be an interesting template to introduce students in the field of statistical physics.

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The physics of computational drug discovery

  1. 1. - The Physics of Drug Discovery - Shourjya Sanyal
  2. 2. Table of Content Topic No Of SlidesIntroduction To Drug 5DesigningMolecular Dynamics 5(MD) SimulationFree Energy 5CalculationsHands on Training :MD Simulation Setup 10and Run
  3. 3. Rational Drug Designing
  4. 4. Rational Drug Designing
  5. 5. Rational Drug Designing
  6. 6. Rational Drug Designing
  7. 7. Rational Drug DesigningAbsorptionDistributionMetabolismElimination
  8. 8. MD SimulationsDynamics: calculating trajectories• Trajectory: positions as function of time: r i (t)• How does one determine r i (t) from Fi = mi . ai ? Fi = mi . Ai = mi . dvi /dti = mi . d2 ri /dti 2• Simple case where acceleration is constant a = dv/dt v = at + vo
  9. 9. MD Simulations Treatment of solvent• Implicit: The macromoleculeinteracts only with itself, but theelectrostatic interactions aremodified to account for the solvent• Explicit representation Themacromolecule is surrounded bysolvent molecules (water, ions) withwhich the macromolecule interacts.Specific nonbond interactions arecalculated
  10. 10. MD Simulations Periodic boundary conditionsFor explicit representation ofsolvent the boundaries of thesystem must be representedfor periodic system.Permits the modeling of verylarge systems, but introducesa level of periodicity notpresent in nature.
  11. 11. MD Simulations
  12. 12. MD Simulations Timescale Limitations Molecular dynamics: Integration timestep - 1 fs, set by fastest varying force. Accessible timescale: about 10 nanoseconds.
  13. 13. Free Energy CalculationsEnergy of binding ∆H must become more negativeThe energetic interactions between ligand andreceptor have to become more favorable
  14. 14. Free Energy CalculationsThe energy terms can be calculated according toforce fields
  15. 15. Free Energy CalculationsDispersive interactions: London forces and van der Waals
  16. 16. Free Energy Calculations
  17. 17. Free Energy Calculations Energy Surface Exploration by Simulation..
  18. 18. MD Simulation SetupMethods for Determining Atomic StructuresNMR (nuclear magnetic resonance) : Absorption of electromagnetic waves
  19. 19. MD Simulation SetupObtaining X-Ray structuresThe arrangement of atoms in the crystal gives rise to adiffraction pattern.
  20. 20. MD Simulation Setup
  21. 21. MD Simulation Setup
  22. 22. MD Simulation SetupStep One: Prepare the Protein Topology> For this tutorial, we will utilize T4 lysozyme L99A/M102Q(PDB code 3HTB). Go to the RCSB website and download thePDB text for the crystal structure.> Seperate out Ligand and Parent Molecule.grep JZ4 3HTB_clean.pdb > JZ4.pdb> Create Topology File for Molecule.pdb2gmx -f 3HTB_clean.pdb -o 3HTB_processed.gro -water spc
  23. 23. MD Simulation SetupStep Two : Prepare the Ligand TopologyFor this tutorial, we will use PRODRG to generate a startingtopology for our ligand, JZ4. Go to the PRODRG site andupload your JZ4.pdb file. The server presents you with severaloptions for how to treat your ligand.> Include topology of ligand; Include ligand topology#include "JZ4.itp"
  24. 24. MD Simulation SetupStep Three : Solvate The System In BoxDefine the boxeditconf -f 3HTB_JZ4.gro -o 3HTB_JZ4_box.gro -bt cubic -d 1.0Adding water ions to the boxgenbox -cp 3HTB_JZ4_box.gro -cs spc216.gro -p -o3HTB_JZ4_boxwater.gro
  25. 25. MD Simulation SetupStep Four : Energy MinimizationNow that the system is assembled, create the binary inputusing grompp using this input parameter file:grompp -f enermin.mdp -c 3HTB_JZ4_boxwater.gro -p -oem.tprWe are now ready to invoke mdrun to carry out the EM:mdrun -v -deffnm em
  26. 26. MD Simulation SetupStep Five : AnalysisEnergy Landscapeg_energy -f em.edr -o tot.xvgStructural Analysisg_rama -f em.trr -s em.tpr -o myrama.xvg
  27. 27. PRESENTATIONDEVELOPMENT Shourjya SanyalAcademic : shourjya.sanyal@ucdconnect.ieBusiness :
  28. 28. Think Biosolution Pvt. Ltd. is a young startup aimed at providing lowcost solutions to enterprise ranging from biotechnology to bio-medicalinstrumentation. We are a global team of young scientists andtechnocrats who aims to serve towards making a better future, byincorporating innovative technology within framework of currentoperations for a given corporation.It is our dream to accelerate technology growth and developmenttowards building a better tomorrow I welcome you all to be a part ofthis dream.