Updates

   
VU MEDICINAL CHEMISTRY

TOOLS AND DOWNLOADS


 


Network issues resolved - we're back!

posted Jan 24, 2017, 7:10 AM by Albert Kooistra

Finally, after 10 days, we are back online!

There was an unfortunate issue with the network of the servers, so they were isolated from the outside world. The KLIFS/PDEStrIAn/3D-e-Chem services are all available again!

Unforeseen downtime of KLIFS, PDEStrIAn, and KRIPO services

posted Jan 17, 2017, 12:40 AM by Albert Kooistra   [ updated Jan 20, 2017, 7:56 AM ]

Last Thursday, January 12th, our servers were successfully upgraded and maintained. However, this Sunday an unforeseen hardware failure occurred in the network, which cut down all communication lines with the outside world. So, despite the fact that our freshly updated servers are eagerly awaiting your requests there is no internet connection available.

We expect that the network issues will be resolved within the next 48 hours. We will keep you posted.

Update 20-01: The problem has been identified and will be resolved coming Monday (23rd of January)

Student Assistantship Programming in Virtual Reality

posted Nov 9, 2016, 6:22 AM by Albert Kooistra   [ updated Nov 9, 2016, 6:24 AM ]

Nature Scientific Reports publication: Computer-aided drug discovery à la carte

posted Jul 6, 2016, 12:39 AM by Albert Kooistra   [ updated Jul 6, 2016, 12:44 AM ]

Researchers from the division of Medicinal Chemistry have developed a new methodology, which not only allows for the in silico discovery of novel ligands for GPCRs, but also for the prediction of the functional effect of those ligands.

The Nature Scientific Reports publication virtual screening methodology combines a conventional energy-based scoring function with a molecular interaction fingerprinting (IFP) technique. This approach, together with the selection of an optimal reference X-ray structure, enabled the prospective identification of histamine H1 receptor antagonists and β2-adrenoceptor agonists.

Picture: Graphical summary of the workflow and application of the published computational method that enables the selective identification of novel GPCR ligands with the desired functional effect.


Dr. Albert J. Kooistra, Dr. Chris de Graaf, and colleagues utilized the growing amount of available GPCR X-ray structures to develop a computational method for the identification of GPCR ligands through virtual screening while simultaneously selecting for a specific functional effect. GPCRs form the largest family of transmembrane proteins encoded for by the human genome and are key drug targets due to their essential regulatory role in signal transduction and cell function. The published approach takes advantage of the increasing structural knowledge regarding the molecular determinants of ligand binding and, more specifically, function-specific binding of agonists, antagonists, and inverse agonists.

The combination of a conventional energy-based scoring function with a molecular interaction fingerprinting (IFP) technique and the optimal reference X-ray structure enabled the prospective identification of 19 histamine H1 receptor antagonists and 18 β2-adrenoceptor agonists. Systematic evaluation of X-ray structures and the optimized combined scoring approach allow, in a sense, to pick new GPCR ligands with high accuracy (hit-rates of 73% for H1R and 53% for β2R) from a database with millions of molecules and also to select the flavor of the ligand (i.e. agonist versus antagonist). Moreover, the performance of the consensus approach was also evaluated by experimentally validating the performance of the individual application of the energy-based as well as the IFP approach. In all cases the consensus methodology resulted in the highest hit-rates and identified compounds with the highest receptor binding affinity and potency.    

This study shows that the combination of cheminformatics approaches and the developments in the structural determination of GPCRs opens up new opportunities for targeted drug discovery. Ultimately, this approach could even be used to predict individual signaling pathways to design optimal biased signaling profiles for ligands of this pharmaceutically important protein family.

Click below to go to the open access article:

Kooistra, A.J., Vischer, H.F., McNaught-Flores, Leurs, R., de Esch, I.J.P., de Graaf, C. Function-specific virtual screening for GPCR ligands using a combined scoring method. Scientific Reports. 6 (2016): 28288.

Back online

posted Feb 29, 2016, 5:47 AM by Albert Kooistra   [ updated Feb 29, 2016, 6:13 AM ]

O|2 building
We have successfully moved to our new research building O|2 (see picture).
The servers are up and running again and the KLIFS and PDEStrIAn websites are available.
Please keep in mind that we might still encounter a few unexpected network issues (including DNS updates) that might influence the stability and reachability of the servers.

Thank you for your patience,
The KLIFS and PDEStrIAn team

Downtime of the KLIFS and PDEStrIAn server

posted Feb 24, 2016, 3:39 AM by Albert Kooistra   [ updated Feb 26, 2016, 7:22 AM ]

Update 26-02: Unfortunately the network is not fully operational thereby extending the downtime till Monday the 29th of February. Our apologies for the inconvenience.

In the week of 22 February - 26 February (and possibly the week after as well) we will move to our new research building O|2. As the servers will also move, we will experience downtime that may range from a few hours to a few days. 

Thank you for your understanding,
The KLIFS and PDEStrIAn team

PDEStrIAN in J. Med. Chem

posted Feb 23, 2016, 11:24 AM by Albert Kooistra

PDEStrIAn: phosphodiesterase (PDE) Structure and ligand Interaction Annotated database
TOC graphic

Our latest manuscript has just been accepted as a "perspective" in Journal of Medicinal Chemistry:

PDEStrIAn: A phosphodiesterase structure and ligand interaction annotated database as a tool for structure-based drug design


The article in its "just accepted" form is available here: http://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.5b01813

PDEStrIAn is currently available as a downloadable dataset from http://pdestrian.vu-compmedchem.nl and the ZENODO repository https://zenodo.org/record/45774

Nucleic Acids Research

posted Oct 24, 2015, 10:31 AM by Albert Kooistra   [ updated Oct 24, 2015, 10:32 AM ]

Our manuscript describing the updated KLIFS database including the web interface has been accepted by Nucleic Acids Research for their database issue of 2016. The article is freely available (open access) from the NAR website: http://nar.oxfordjournals.org/content/early/2015/10/22/nar.gkv1082.full.html

1 July 2015: The new web-based version of KLIFS is now online!

posted Jul 1, 2015, 3:12 AM by Albert Kooistra   [ updated Oct 22, 2015, 12:33 AM ]

The new (and web-based) version of KLIFS is now freely accessible @ http://klifs.vu-compmedchem.nl!

This new version of KLIFS contains lots of new features, including:
  • Weekly updates!
  • Over 2800 kinase domain structures
  • Mouse kinase domains (and more species to come)!
  • Curated and corrected ligand structures
  • Improved accuracy of the Interaction Fingerprints
  • Improved superposition of each structure
  • Better sequence alignment and pocket selection
  • Analysis and annotation of waters in the pocket
  • A website that enables quick and easy access to all the data and to analyse and compare all the data efficiently
  • Many features that you can use to explore the kinase data (e.g. interaction search, ligand (sub)structure search, water clusters search)
  • And much more...
Thank you for your patience while we were working on this new version. We hope that you will enjoy KLIFS version 2 @ http://klifs.vu-compmedchem.nl. Please let us know if you have any comments, remarks, or ideas via the feedback options on the website.

The KLIFS team

Next week: KLIFS v2.0 online

posted Jun 22, 2015, 3:44 AM by Albert Kooistra

KLIFS
After several delays the webserver is finally ready to go public! 

We are currently reprocessing all kinase structures and we will go live next week. As we already outlined in a previous post this new version will bring lots of new structures (and it will keep up to date), but more importantly it is now very easy to search, browse and download the KLIFS data using the web interface!

We hope you will be back very soon,

The KLIFS team






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