Introduction

This document provides a guide on running a large-scale virtual screen using the DOCK software suite.

This guide is not meant to encompass every single script and process that exists in our lab, but instead is meant to bring a user through the main stages of running a docking screen. Where available, we provide links to wiki pages that contain more details/program options/etc. We also provide access to old documents from the lab which contain years of scripts and processes. But be warned, these documents may be out of date and hard to follow. If you find yourself using something not in this document very frequently, please inform us and we can add it.

The workflow is broadly divided into five main stages: protein preparation, retrospective docking, large-scale docking (LSD), filtering, and experimental testing. We provide a general description of each stage, but each section in the following document contains many more details.

Protein Preparation

Protein preparation is the process of protonating and cleaning PDB structures for use in molecular docking.

Retrospective Docking

Retrospective docking serves the dual purpose of sanity check and optimization. We want to make sure that our docking setup using our protein structure scores known binders better than decoys, which are molecules presumed not to bind. We also optimize our docking setup to try and achieve the best enrichment of actives over decoys.

Large-Scale Docking (LSD)

After validating that the docking setup is capable of enriching actives over decoys, we use our docking setup to dock and evaluate the ultra-large ZINC database of molecules.

Filtering Stage

The final stage focuses on processing and analyzing the results from large-scale docking to identify promising candidates. It encompasses:

  1. Interaction Filtering: Filtering for molecules that form/don’t form specific defined interactions.

  2. Novelty Filtering: Filtering for molecules that are novel compared to known binders.

  3. Clustering: Ensuring that the molecules we order are diverse.

  4. Hit-Picking: Manually visualizing docking poses to select the most promising molecules for experimental testing.

Experimental Testing

The ultimate test of your docking screen is finally the experimental testing of your picked molecules. We provide some advice for things to look out for.