Revision as of 17:53, 18 March 2023

Introduction

This tutorial is a continuation of the virtual screening tutorial. In this tutorial, we'll continue to work with the receptor and ligand in PDB 3WZE, and we'll attempt to generate new ligands for the receptor using three kinds of de novo design: de novo refinement, focused de novo design, and generic de novo design.

De novo can be directly translated as "of new", but a more deft translation might be "from the beginning" or "from scratch". This method of ligand generation involves procedurally generating a a ligand using algorithms within programs like DOCK, and is typically used to build entirely new ligands for proteins by building molecules outwards from an initial anchor one moiety at a time.

Generic de novo design best matches the prior description, in which a pre-selected or random anchor is positioned within the active site of the receptor, and then built outwards in a number of layers occupied by various sampled moieties. Focused de novo design is much like generic de novo design, except that the pool of sampled moieties is curtailed to suit the needs of the researcher. Finally, de novo refinement is when one begins with an already discovered ligand, then deletes some of the molecule and replaces it with a dummy atom, effectively using the remainder of the ligand as the anchor for the de novo design algorithms to modify.

Directories

Make a new directory for de novo refinement:

 mkdir 009_denovo

De Novo Refinement

Ligand Preparation

1. Open the final, energy minimized ligand mol2 file which was used for the virtual screen tutorial, and also open the final receptor mol2 file that was used in that screen. As long as no translations or rotations have occurred during the virtual screen process, the ligand should still be in its native orientation within the receptor's active site, as depicted by the original 3WZE pdb file.

2. Examine the binding pocket of the receptor, and choose a part of the 3WZE ligand that faces towards the interior of the binding pocket. Parts of the ligand that are innermost to the receptor make for the best parts to delete because they tend to have the most potential interactions with the protein, allowing the various groups tested in de novo design to have a better chance of interacting with a group on the protein. Choosing a part of the ligand to delete which faces the cytosol or the channel leading to the cytosol will be less likely to yield new ligands that can bind tightly to the interior of the receptor.

3. By hovering your mouse cursor

Focused De Novo Design

Generic De Novo Design