Difference between revisions of "2018"

Revision as of 16:46, 1 February 2017

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.

3PGL

In this tutorial we will use PDB code 4QMZ, the deposited crystal structure of human small C-terminal domain Phosphatasee 1 bound to rabeprazole.

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-Spring2016/dock-tutorial/00.files/
                                         /01.dockprep/
                                         /02.surface-spheres/
                                         /03.box-grid/
                                         /04.dock/
                                         /05.large-virtual-screen/
                                         /06.virtual-screen/
                                         /07.footprint/
                                         /08.print_fps

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, '3PGL'. The following sections in this tutorial will adhere to this directory structure/naming scheme.

II. Preparing the Receptor and Ligand

Download the PDB file (3PGL) from the protein databank: RCSB.org

3pgl.pdb was moved into 00.files

3pgl.pdb was copied to raw_3pgl.pdb. The header and all lines that don't start with ATOM or HETATM were deleted; all instances of HETATM were changed to ATOM. The second domain (chain B), all the water molecules, and the Mg ion were removed from the PDB file. "RZX A" was changed to "LIG B".

raw_3pgl.pdb was loaded into Chimera; Tools > Structure Editing > AddH used to add hydrogens to the system. Then add charge using Tools > Structure Editing > Add Charge, be sure to change AMBER ff14SB to AMBER ff99SB. Net charge was kept at 0. Save this file as 3pgl.dockprep.mol2.

Preparing the Receptor File

Open 3pgl.dockprep.mol2 in Chimera, select and delete the ligand. Save this file as 3pgl.rec.mol2 in 01.dockprep.

Creating the Ligand File

Open 3pgl.dockprep.mol2 in Chimera, select and delete the receptor (protein), and save this file as 3pgl.lig.mol2 in 01.dockprep.

Creating the noH Receptor File

Open 3pgl.dockprep.mol2 in Chimera, select H atoms through select > element > H, and delete. Save as 3pgl.rec.noH.pdb