Revision as of 10:20, 18 February 2023

Introduction

This tutorial will walk you through the steps necessary for using the DOCK software package. Many drugs are small molecular compounds that attach, or bind, to a protein in our bodies to change how that protein functions. By changing the function of a protein we can treat disease and help people manage symptoms of disorders. Traditionally drug discovery was done through a type of "trial and error" process called High Throughput Screening. Scientists would chemically make, or buy, thousands of small compounds and expose them to cells. They would then observe how the cells responded, either favorably/unfavorably/no effect. This method is time consuming and expensive. It would be better if the scientific community could "virtually screen" these molecules using a computer before creating/buying them - thereby focusing the cost and effort on those which showed the most promising computational results. The DOCK software brings this drug discovery process into the 21st century and uses computers to bind these small molecular compounds to a protein and evaluate the results. DOCK uses algorithms to bring together the small molecule, known as the ligand, and the larger protein, and "DOCK" them together. Our tutorial will walk you through preparing a protein and ligand for docking using an example complex from the protein data bank (https://www.rcsb.org/), complex # 4S0V.

The following steps will be followed:

1. Setting up your environmnet
2. Downloading a protein from the PDB database
3. Determining if there are any missing loops and if they need to be modeled
4. Preparing the ligand
5. Preparing the protein

Learning Objectives

• Understand why DOCK was created and its current role in drug design
• Gain the ability perform virtual screening of small molecular compounds to a protein from the Protein Data Base (https://www.rcsb.org/)

Setting Up Your Environment

Downloading a protein from the PDB database

To begin we need to download protein complex #4S0V from the PDB. The right side of the top banner has a search bar:

Simply type 4S0V into the search bar and the protein complex will be displayed.

On the right hand side, click on Download Files, then PDB Format.

That's it! The pdb file that we will be working with is now downloaded onto your local computer.

Preparation of the ligand and protein

Evaluating the Structure

Preparing the Protein file

Preparing the Ligand File

Checking Hydrogen Atoms and Atom Charges

Creating the Protein Binding Site Surface

Creating the Required Surface (DMS) File

Generating Spheres for the Binding Site

Selecting the Appropriate Spheres

Generating the Required Box and Grid

Generating the Box

Generating the Grid

Docking

Energy Minimization Steps

Footprint Analysis

Rigid Docking

Fixed Anchor Docking

Flexible Docking

Virtual Screening a Library of Available Ligands

Virtual Screeni mpi

Virtual Screening Output

Cartesian Minimization

Docked Molecules Rescoring