2023 DOCK tutorial 2 with PDBID 3WZE

In this tutorial, you will learn how use the program DOCK6.10 to perform a virtual screen, in which you assess how well the molecules in a library of drug-like molecules bind to a protein of known structure.

Introduction

A protein whose function is found to be involved in one or more diseases may become a target for pharmaceutical design. Oftentimes, these pharmaceuticals are designed to compete with the enzyme's native substrate for the enzyme's active site, making many pharmaceutical molecules competitive inhibitors of their protein targets. If the target protein's structure is known, and the active site can be identified, then performing a virtual screen can be a monetarily and temporally efficient method of identifying molecules which are likely to bind well to the target's active site.

A virtual screen is set up by first preparing the enzyme's structure and the structure of its native substrate for docking, then the residues important for the native ligand to bind are identified by generating a footprint. A large library of drug-like molecules is then downloaded from a database such as ZINC [REFERENCE], and, using the footprint and enzyme structure, docked into the enzyme using a program such as DOCK6.10 [REFERENCE]. Results are then assessed to see which drug-like compounds match the native substrate's footprint profile and which are energetically comfortable within the simulated active site. Such molecules could then be tested biochemically for their ability to inhibit the target protein, sparing biochemists the hassle of having to test hundreds of thousands of compounds in physical screening experiments.

Software

ChimeraX (optional)

Chimera is now no longer actively developed, and has been succeeded by ChimeraX, which is developed by the same group [REFERENCE]. Although ChimeraX has lost some of the functionality of its predecessor, it has new capabilities to compensate, and it is easier to operate using typed commands, whereas Chimera requires clicking through menus. That being said, Chimera is still required for this tutorial because ChimeraX cannot open .sph files and it cannot save a surface as a .dms file.