Webinar: High-Confidence Protein−Ligand Complex Modeling by NMR Guided Docking Enables Early Hit Optimization (2018-05-10)

BioExcel’s webinar series continue with a presentation by Andrew Proudfoot, Novartis



Structure-based drug design is routinely used in modern day drug discovery. However, the success of this process is very much dependent upon the ability to generate protein-ligand co-structures.  While NMR and EM can be used to obtain these structures, such techniques can often be labor intensive and are limited to certain subsets of targets.  X-ray crystallography is therefore routinely the method of choice for obtaining co-structures but also contains caveats in that the success rates, when working with dynamic proteins or solubility limited ligands, is often variable.  The lack of structural information obtained for these scenarios makes optimization of the ligand challenging and impacts the diversity of chemical space explored, since such chemical scaffolds are generally not pursued.  To address this, we have developed a robust NMR restraint guided docking protocol which uses HADDOCK to generate high-quality models of protein−ligand complexes.  The use of highly methyl labeled protein facilitates the experimental determination of intermolecular distance restraints between the protein and bound small molecule, which can be used to both drive the docking process and to determine the correct conformation of the ligand in the bound state.  In addition, we show that the models produced by this method are of sufficient accuracy to drive a structure-based drug campaign through the successful optimization of crystallographically intractable fragment hits into more potent binders.


Andrew Proudfoot, Novartis


Andrew Proudfoot

In 2012 I completed my PhD at the University of Sheffield where, working with Professor Michael Williamson I used NMR to perform structural studies of the enzyme NADPH-Protochlorophyllide Oxidoreductase.  After completing my PhD I moved to America where I have performed postdoctoral research in Kurt Wüthrich’s laboratory, at the Scripps Research Institute (TSRI), and at Novartis Institutes for BioMedical Research (NIBR).  During my time at TSRI I used NMR to study the structure of proteins which had unknown functions, as well as studying protein-DNA complexes involved with the regulation of stem cell differentiation.  Since moving to NIBR, the focus of my research has changed to use both structural and biophysical techniques to characterize and optimize protein-ligand interactions as well as non-structural viral proteins.  This includes the de novo structure solution of proteins using X-ray crystallography, the development of new selective labeling protocols to maximize the amount of information that can be obtained from a single NMR sample along with the implementation of docking protocols to produce models of protein-ligand complexes, which can be used to drive structure based drug design.


Register for webinar

Title: High-Confidence Protein−Ligand Complex Modeling by NMR Guided Docking Enables Early Hit Optimization

Date: 10th May, 2018
Time: 14:00 BST / 15:00 CET

Registration URL: https://attendee.gotowebinar.com/register/4066833316534085122

Webinar ID: 745-584-923


You will then receive an email with details of how you can connect to the webinar.

Discuss this webinarView slides on SlideShare Join Interest Group

Leave a Reply