- The Physics of Drug Discovery -

Shourjya Sanyal

Table of Content

Topic No Of Slides

Introduction To Drug Designing

5

Molecular Dynamics (MD) Simulation

5

Free Energy Calculations

5

Hands on Training :

MD Simulation Setup and Run

10

Rational Drug Designing

Rational Drug Designing

Rational Drug Designing

Rational Drug Designing

Rational Drug Designing

Absorption Distribution Metabolism Elimination

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 + v

o

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

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.

MD Simulations

MD Simulations

Molecular dynamics:Integration timestep - 1 fs, set by fastest varying force.

Accessible timescale: about 10 nanoseconds.

Timescale Limitations

Free Energy Calculations

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

Free Energy Calculations

The energy terms can be calculated according to force fields

Free Energy Calculations

Dispersive interactions: London forces and van der Waals

Free Energy Calculations

Free Energy Calculations

Energy Surface Exploration by Simulation..

MD Simulation Setup

Methods for Determining Atomic Structures

NMR (nuclear magnetic resonance) : Absorption of electromagnetic waves

MD Simulation Setup

Obtaining X-Ray structures

The arrangement of atoms in the crystal gives rise to a diffraction pattern.

MD Simulation Setup

MD Simulation Setup

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

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"

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

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

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

PRESENTATION DEVELOPMENT

Shourjya SanyalAcademic : shourjya.sanyal@ucdconnect.ieBusiness : shourjya@thinkbiosolution.com

Think Biosolution Pvt. Ltd. is a young startup aimed at providing low cost solutions to enterprise ranging from biotechnology to bio-medical instrumentation. We are a global team of young scientists and technocrats who aims to serve towards making a better future, by incorporating innovative technology within framework of current operations for a given corporation.It is our dream to accelerate technology growth and development towards building a better tomorrow I welcome you all to be a part of this dream.

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