XClose

UCL School of Pharmacy

Home
Menu

Covid-19 drug discovery projects

A new coronavirus, named SARS CoV-2 that causes the Covid-19 disease has led to a global pandemic with severe socio-economic consequences.

7 September 2020

As of late July, more than 17 million people have been infected and more than 660,000 have died worldwide. Virtually no country in the world has been protected from the devastating effects of this new SARS virus strain, which mostly targets the elderly or people with pre-existing medical conditions. 

Huge global efforts are under way to develop vaccines against Covid-19 and to repurpose existing antiviral drugs through a variety of clinical trials. These efforts have led to the identification of remdesivir and dexamethasone, which both have shown some positive effects in treating Covid-19 patients, but neither represents a “magic bullet". Currently, there are no effective vaccines or drugs available to prevent or treat Covid-19 infections. Therefore, an important strategy is to identify and develop new drugs that target SARS CoV-2, to combat and contain future SARS outbreaks. 

Our network at UCL School of Pharmacy is contributing to the understanding of SARS CoV-2 structure and function and all stages of the early-stage drug discovery and development process.

Currently, we are working on proteins of the viral RNA capping machinery such as non-structural protein 10 (nsp10), the bimodular protein nsp14 that contains 3’-to-5’ exoribonuclease and N7-methyltransferase domains and nsp16 that has 2’-O-methyltransferase activity. Nsp10 acts as an activator of nsp14 and nsp16. In addition, we are also open to working on other potential coronavirus and SARS CoV-2 drug targets.

Prof. Frank Kozielski’s (f.kozielski@ucl.ac.uk) group is interested in the early stages of drug development including inhibitor/fragment screening, the biophysical and biochemical characterisation of protein-inhibitor/ fragment complexes, drug optimisation using structure-based drug design, and by determining crystal structures of potential Covid-19 protein targets. For example, recently we determined the crystal structure of SARS CoV-2 nsp10 and characterised its behaviour in solution (Rogstam et al., submitted). This structure will serve as a basis for fragment-based screening (Figure 1). Three new PhD students will work on various Covid-19 protein targets.     

The crystal structure of unbound SARS CoV-2 non-structural protein 10 at 1.6 Å resolution.

Figure 1: The crystal structure of unbound SARS CoV-2 non-structural protein 10 at 1.6 Å resolution. The structure will be used for structure-based drug design (Figure taken from [1].    

Prof. Shozeb Haider (shozeb.haider@ucl.ac.uk) uses computational modelling techniques including molecular dynamics simulations, building markov state models, metadynamics and artificial intelligence methods to contribute to the understanding the dynamics of SARS CoV-2 proteins and complexes, the identification of inhibitor binding pockets, and the molecular docking of inhibitors to guide the synthesis of new inhibitor analogues to target Covid-19. For example, computational modelling proposes the existence of a potential binding pocket at the interface between non-structural proteins 10 and 14 (Figure 2). A current PhD student, Huan Wang is working on modelling Covid-19 proteins.

 

 

Molecular dynamics simulations of nsp10-nsp14 complex.

 

Figure 2: Molecular dynamics simulations of nsp10-nsp14 complex. (A) A working model of nsp10 (red) - nsp14 (green) complex has been simulated in explicit solvent to sample its conformational landscape. (B) Dynamic pockets were identified in the nsp14 (pocket1 - blue) that can be exploited for virtual screening. However, additional pockets (pocket2 – yellow) are formed at the nsp10-nsp14 interface. These pockets can be exploited to design protein-protein interface inhibitors, which could regulate the influence of nsp10 on nsp14 activity. (C) RMSD plot of nsp10 (red) and nsp14 (green) from the MD simulation, highlighting the stability of the complex.

Dr. Geoff Wells (g.wells@ucl.ac.uk) and his group are medicinal chemists who complement the research work, by synthesising novel inhibitor analogues targeting Covid-19 protein targets. They also use modelling techniques for the selection of new inhibitor analogues prior to synthesis balancing potency with good drug-like properties. All three groups work closely together in this highly interdisciplinary academic drug discovery project.  

We have several collaboration partners with whom we work together on various aspects of the larger project including Dr. Wolfgang Knecht (Lund University, Sweden; https://portal.research.lu.se/portal/en/persons/wolfgang-knecht(f1379bc0-f82a-4384-ab5a-eda6cd6996bb).html), Dr. Zoe Fisher (European Spallation Source (ESS), Sweden; https://europeanspallationsource.se/profile/zoe-fisher) and Dr. Michela Mazzon (Virology Research Services Ltd; https://uk.linkedin.com/company/virologyresearchservices?trk=public_prof...), who is developing cellular assays for Covid-19 research.  

For enquiries about PhD projects or collaboration opportunities, please contact members of the Covid-19 research network.
 

Science highlights and references related to this Covid-19 project
Recent Science Highlights at LENS: https://www.lens-initiative.org/2020/05/15/prioritised-support-from-ess-...
Recent Science Highlights at the Max IV synchrotron Facility:
https://www.maxiv.lu.se/news/tackling-sars-cov-2-viral-genome-replicatio...

Recent Science Highlights at the European Spallation Source (ESS): https://europeanspallationsource.se/article/2020/05/14/large-scale-resea...

The coordinates are now available at the Protein Data Bank under accession number 6ZCT: https://www.rcsb.org/structure/6ZCT
 
The relevant data has also been shared with the research community at the Covid-19 data portal Sweden and the deposited data (PDB:6ZCT) can be found listed in the protein data module: https://covid19dataportal.se/data_types/protein_data/data/

The project is supported by the MAX IV rapid access call COVID-19, https://www.maxiv.lu.se/covid-19/, and the ESS DEMAX call for prioritized projects related to COVID-19 research: https://europeanspallationsource.se/article/2020/03/27/ess-demax-lab-pri...


[1] Annika Rogstam, Maria Nyblom, Signe Christensen, Celeste Sele, Vladimir O. Talibov, Therese Lindvall, Anna Andersson Rasmussen, Ingemar André, Zoë Fisher, Wolfgang Knecht, Frank Kozielski. Structure of Non-Structural Protein 10 from Severe Acute Respiratory Syndrome Coronavirus-2. Manuscript submitted.