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.

1. - The Physics of Drug Discovery -
Shourjya Sanyal

2. Table of Content
Topic No Of Slides
Introduction To Drug 5
Designing
Molecular Dynamics 5
(MD) Simulation
Free Energy 5
Calculations
Hands on Training :
MD Simulation Setup 10
and Run

3. Rational Drug Designing

4. Rational Drug Designing

5. Rational Drug Designing

6. Rational Drug Designing

7. Rational Drug Designing
Absorption
Distribution
Metabolism
Elimination

8. MD Simulations
Dynamics: 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. MD Simulations
Treatment of solvent
• Implicit: The macromolecule
interacts only with itself, but the
electrostatic interactions are
modified to account for the solvent
• Explicit representation The
macromolecule is surrounded by
solvent molecules (water, ions) with
which the macromolecule interacts.
Specific nonbond interactions are
calculated

10. MD Simulations
Periodic boundary
conditions
For explicit representation of
solvent the boundaries of the
system must be represented
for periodic system.
Permits the modeling of very
large systems, but introduces
a level of periodicity not
present in nature.

11. MD Simulations

12. MD Simulations
Timescale Limitations
Molecular dynamics:
Integration timestep - 1 fs, set by
fastest varying force.
Accessible timescale: about 10
nanoseconds.

13. Free Energy Calculations
Energy of binding ∆H must become more negative
The energetic interactions between ligand and
receptor have to become more favorable

14. Free Energy Calculations
The energy terms can be calculated according to
force fields

15. Free Energy Calculations
Dispersive interactions: London forces and van der Waals

16. Free Energy Calculations

17. Free Energy Calculations
Energy Surface
Exploration by Simulation..

18. MD Simulation Setup
Methods for Determining Atomic Structures
NMR (nuclear magnetic resonance) : Absorption of electromagnetic waves

19. MD Simulation Setup
Obtaining X-Ray structures
The arrangement of atoms in the crystal gives rise to a
diffraction pattern.

20. MD Simulation Setup

21. MD Simulation Setup

22. MD Simulation Setup
Step 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 the
PDB 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. MD Simulation Setup
Step Two : Prepare the Ligand Topology
For this tutorial, we will use PRODRG to generate a starting
topology for our ligand, JZ4. Go to the PRODRG site and
upload your JZ4.pdb file. The server presents you with several
options for how to treat your ligand.
> Include topology of ligand
; Include ligand topology
#include "JZ4.itp"

24. MD Simulation Setup
Step Three : Solvate The System In Box
Define the box
editconf -f 3HTB_JZ4.gro -o 3HTB_JZ4_box.gro -bt cubic -d 1.0
Adding water ions to the box
genbox -cp 3HTB_JZ4_box.gro -cs spc216.gro -p 3HTB_JZ4.top -o
3HTB_JZ4_boxwater.gro

25. MD Simulation Setup
Step Four : Energy Minimization
Now that the system is assembled, create the binary input
using grompp using this input parameter file:
grompp -f enermin.mdp -c 3HTB_JZ4_boxwater.gro -p 3HTB_JZ4.top -o
em.tpr
We are now ready to invoke mdrun to carry out the EM:
mdrun -v -deffnm em

26. MD Simulation Setup
Step Five : Analysis
Energy Landscape
g_energy -f em.edr -o tot.xvg
Structural Analysis
g_rama -f em.trr -s em.tpr -o myrama.xvg

27. PRESENTATION
DEVELOPMENT
Shourjya Sanyal
Academic : shourjya.sanyal@ucdconnect.ie
Business : shourjya@thinkbiosolution.com

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