2015 DOCK tutorial with Poly(ADP-ribose) polymerase (PARP)

For additional Rizzo Lab tutorials see DOCK Tutorials. Use this link Wiki Formatting as a reference for editing the wiki. This tutorial was developed collaboratively by the AMS 536 class of 2014, using DOCK v6.6.

I. Introduction

DOCK

DOCK is a molecular docking program used in drug discovery. It was developed by Irwin D. Kuntz, Jr. and colleagues at UCSF (see UCSF DOCK). This program, given a protein binding site and a small molecule, tries to predict the correct binding mode of the small molecule in the binding site, and the associated binding energy. Small molecules with highly favorable binding energies could be new drug leads. This makes DOCK a valuable drug discovery tool. DOCK is typically used to screen massive libraries of millions of compounds against a protein to isolate potential drug leads. These leads are then further studied, and could eventually result in a new, marketable drug. DOCK works well as a screening procedure for generating leads, but is not currently as useful for optimization of those leads.

DOCK 6 uses an incremental construction algorithm called anchor and grow. It is described by a three-step process:

1. Rigid portion of ligand (anchor) is docked by geometric methods.
2. Non-rigid segments added in layers; energy minimized.
3. The resulting configurations are 'pruned' and energy re-minimized, yielding the docked configurations.

1HVR Receptor surface

Poly ADP Ribose Polymerase (PARP)

Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes involving mainly DNA repair and programmed cell death. (Wikipedia: http://en.wikipedia.org/wiki/Poly_ADP_ribose_polymerase) The particular PARP family member we will focus on is PARP5b (aka: Tankyrase 2) of which the catalytic domains contains 227 amino acid residues. Olaparib (AZD-2281, trade name Lynparza) is an FDA-approved chemotherapeutic agent, developed by KuDOS Pharmaceuticals and later by AstraZeneca. It is an inhibitor of poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair.[1] It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which includes many ovarian, breast, and prostate cancers. (Wikipedia: http://en.wikipedia.org/wiki/Olaparib)

In this class, we will perform docking experiments and virtual screening on a crystallographic structure of PARP5b in complex with a small-molecule inhibitor, olaparib (PDB ID: 4TKG).

Organizing Directories

While performing docking, it is convenient to adopt a standard directory structure / naming scheme, so that files are easy to find / identify. For this tutorial, we will use something similar to the following:

~username/AMS536/dock-tutorial/00.files/
                              /01.dockprep/
                              /02.surface-spheres/
                              /03.box-grid/
                              /04.dock/
                              /05.mini-virtual-screen/
                              /06.virtual-screen/
                             

In addition, most of the important files that are derived from the original crystal structure will be given a prefix that is the same as the PDB code, '4TKG'. The following sections in this tutorial will adhere to this directory structure/naming scheme.

II. Preparing the Receptor and Ligand

Matt Elmes

Courtney Singleton

III. Generating Receptor Surface and Spheres

Kellon Belfon

Xingyu

IV. Generating Box and Grid

Box Generation

• Make a new directory and name it: 03.box-grid/

   mkdir 03.box-grid

• Make a new file in this directory and name it showbox.in

   vim showbox.in

• This will automatically open the file showbox.in. Edit the file showbox.in as follows:

   Y                                               # Yes, generate a box
   8.0                                             # Size of the box in Angstroms
   ../02.surface-spheres/selected_spheres.sph      # Sphere.sph file
   1                                               # Cluster number
   1HVR.box.pdb                                    # Name of the output file

• Save the file using the command:

    :wq

in esc mode

• Run the command:

    showbox < showbox.in

figure waiting...

Cong Liu

V. Docking a Single Molecule for Pose Reproduction

Michael Cortes

Beibei Zhang

Prajna Shanbhogue

VI. Virtual Screening

george jones

Sam Chiappone