Mpro Files
Carmen Kalua
Are you having problems opening a MPRO file or are you simply curious about its contents? We're here to explain the properties of these files and provide you with software that can open or handle your MPRO files.
While we do not yet describe the MPRO file format and its common uses, we do know which programs are known to open these files, as we receive dozens of suggestions from users like yourself every day about specific file types and which programs they use to open them.
We are continually working on adding more file type descriptions to the site, so if you have information about MPRO files that you think will help others, please use the Update Info link below to submit it to us - we'd love to hear from you!
These apps are known to open certain types of MPRO files. Remember, different programs may use MPRO files for different purposes, so you may need to try out a few of them to be able to open your specific file.
Not sure exactly what type of file you are trying to open? Try our new File Analyzer. It is a free tool that can identify more than 11,000 different kinds of files - most likely yours too! It will help you find software that can handle your specific type of file. Download File Analyzer here.
I've previously described the fragment hits from a fragment screen against crystals of the main protease (MPro) of SARS-CoV-2, the virus that causes COVID-19. Full details of the screening effort are described here -19/for-scientists/Main-protease-structure-and-XChem/Downloads.html
I've downloaded all the structures that were screened, both those that bind and those where no binding was observed and put them into a single file, also added inChiKey, SMILES, PubChem ID, PDB ID of ligand if known and a range of other identifiers from different databases, the file is available here
Whilst that is probably sufficient for those looking at cheminformatics driven approaches to designing new molecules anyone wanting to undertake structure based design would need to download all the structures and then overlay them to visualise on their desktop. Fortunately Manish Sud of MayaChemTools has done the hard work and generated a series of PYMOL session files that allow you explore the enzyme crystal structure and the screening data interactively.
The PyMOL session files are setup to facilitate the analysis of protein ligand interactions in the binding pocket, to view the files select "Open" from the file menu bar, some of the larger files make take a little while to load.
It is likely that fragments will only have very modest affinity and that to completely suppress the enzyme it will require very high affinity ligands with good pharmacokinetics to achieve 100% occupancy for 24 hours per day. For this reason molecules that irreversibly bind to the enzyme might be an attractive alternative option.
Whilst much of drug discovery deals with non-covalent, reversible interactions with the target protein there are also a class of therapeutic agents that bind covalently to the target protein, these are described on this page. To mitigate the risk of off-target toxicity you will need to maximise the selectivity for the target enzyme. Glutathione conjugation can be used as a surrogate for off-target reactivity.
Designs will be prioritized by factors, such as ease of synthesis, and toxicity modeling, then synthesized by Enamine and tested by groups around the world. PostEra will be running machine learning algorithms in the background to triage suggestions and generate synthesis plans to enable a rapid turnaround. You will be informed of the progress of the molecules through the main stages (validation, synthesis and testing).
This page contains information of specific interest to MPRO members only.If you are a visitor, feel free to browse but please do not touch the merchandise!NEW: See bottom of page for new Instrument Lending Library program for Participating Members!MPRO Membership Types and DuesThe MPRO membership types, with corresponding yearly dues, are as follows:
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The mpro-members list is a private list for current participating and associate MPRO members to communicate together for orchestra announcements, sharing interesting posts, etc. This list is also used to distribute music, part assignments, midi files and information regarding meetings, rehearsals and concerts.
This tutorial provides a companion to the work performed in March 2020 by InformaticsMatters, the Diamond Light Source, and the European Galaxy Team to perform virtual screening on candidate ligands for the SARS-CoV-2 main protease (MPro). This work is described in our dedicated site.
In this tutorial, you will perform protein-ligand docking to MPro using rxDock (Ruiz-Carmona et al. 2014), a version of the popular rDock software, and score the results using two different methods. The same tools will be used as in the original study, but with a smaller dataset.
Early in March 2020, the Diamond Light Source completed a successful fragment screen on MPro, which provided 55 fragment hits (see their press release here). In an effort to identify candidate molecules for binding, InformaticsMatters, the XChem group and the European Galaxy team joined forces to construct and execute a Galaxy workflow for performing and evaluating molecular docking on a massive scale.
An initial list of 41,000 candidate molecules was assembled by using the Fragalysis fragment network to elaborate from the initial fragment hits, as described in their documentation. These were used as inputs for the docking and scoring workflow. The workflow consists of the following steps, each of which was carried out using tools installed on the European Galaxy server:
The original study required almost 20 years of CPU time, not counting GPU resources consumed. This is obviously not reproducible as a tutorial. Therefore, we will repeat the workflow with a small library of just 100 molecules, on a single MPro fragment structure. Links will be provided to original Galaxy histories, with notes to explain where and why things were done differently to the tutorial.
Of the initial 55 fragment hits, 17 were chosen for further study. From these, 41,587 compounds were generated using the Fragalysis fragment network for further study. The 100 compounds used in the tutorial are taken from this list.
This history contains 103 files. One of these (Initial candidates for docking) contains the 41k candidate compounds in SMILES format. The remaining 102 files (all with names beginning with Mpro-x...) provide structural information on the fragment hits - 6 files per hit (hence 17 x 6 = 102).
The PDB file of the receptor that we are using is Mpro-x0195_0_apo-desolv.pdb. In other words, the structure is derived from just one fragment hit. In the original study, however, all compounds were docked against all of the fragment hit structures.
Before docking, the candidate ligands need to be prepared for docking with the following steps: 1) charge enumeration, 2) generation of three-dimensional structures, and 3) splitting the SD-file into a collection.
So far our list of enumerated candidate compounds is still in SMILES format; we need to produce three-dimensional structures in SDF format for docking. This can be done with the Compound conversion tool tool.
The rxDock tool performs one docking at a time (more technically: the task is not parallelized, as it uses only a single CPU). Therefore, splitting the large SD-file into many small files allows the work to be carried out by multiple Galaxy jobs in parallel, so it completes faster.
In the original study, this kind of parallelization was absolutely essential because of the enormous dataset; at some points, there were 5,000 docking jobs running concurrently on the European Galaxy server. Even on the much smaller scale of this tutorial, we can speed things up considerably using this trick.
This stage was carried out as described here. However, it was repeated for each of the fragment hit structures, not just the Mpro-x0195_0_apo-desolv.pdb file used here. See the active site prep workflow for more details.
The Frankenstein ligand combines the atoms of all the fragments and therefore occupies the entire space of the binding site. Therefore, it is the best choice for cavity definition. See the information provided by InformaticsMatters for more details.
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