Category Archives: science news

Structure-based drug design updates for SARS-CoV-2

I will be posting here information that is published regarding available crystal structures from SARS-CoV-2 and any other information relevant to structure-based drug design against the virus. Key proteins and their roles in viral infection can be found here. I hope you find this informative and useful for your research.

25 March 2020: 68 crystal structures of SARS-CoV-2 protease, with various bound fragments identified using PanDDA analysis are listed here by EBI.

25 March 2020: The Diamond Light Source (UK) has been able to solve a new structure of the SARS-CoV-2 main protease (MPro) at high resolution (1.25 Å, PDB ID: 6YB7), and subsequently complete a large XChem crystallographic fragment screen against it (detailed here). Data have been deposited with the PDB, and are made available immediately to the world on this page; additional work is ongoing, and updates will be continually posted in their website. On Tuesday March 17th they publicly released results from the full 1500-crystal experiment that yielded 58 non-covalent and covalent active-site fragments. Following data reprocessing and further analysis, an additional 13 structures were released on March 24th taking the final total to 66 active site fragments, 44 of which were covalently bound (full timeline heredownload page here). This was an exceptionally large screen, and yielded an exceptionally rich readout, with vast opportunities for fragment growing and merging.


25 March 2020: Blog post, with code by Patrick Walters in Practical Cheminformatics “Building on the Fragments From the Diamond/XChem SARS-CoV-2 Main Protease (MPro) Fragment Screen (Part I)” . Share schemoinformatics techniques and the code used when working with the results of fragment screens.

25 March 2020: Visualize SILCS FragMaps for the SARS-CoV-2 main protease (PDB ID 6LU7) through the SILCS demo web viewer, and check out the 6LU7 crystallographic ligand and the XChem fragment screen results from the Diamond Light Source.




24 March 2020: Results of Diamond Light Source fragment screen:There were 68 hits of high interest – data and extensive details are here, and some interactive views here:

  • 22 non-covalent hits in the active site
  • 44 covalent hits in the active site
  • 2 hits in the dimer interface, one in a calculated hotspot

Based on these data, the team invites chemists around the world to design new compounds or present existing compounds that could bind to the protease and submit them here.Structures submitted are prioritized by factors such as ease of synthesis and potential toxicity and the compounds selected will be synthesized and evaluated for binding to the SARS-CoV-2 protease.

Screen Shot 2020-03-27 at 2.20.38 PMResults from the XChem fragment screen of the Diamond Light Source can be found here.


20 March 2020: The crystal structure of SARS-CoV-2 main protease is published complexed with an α-ketoamide inhibitor (PDB ID: 6Y7M). The main viral protease (Mpro, also called 3CLpro) is one of the best characterized drug targets among coronaviruses. 3CLpro protease is required for the virus but lacks human homologous proteins and thus inhibitors of this protease are less likely to bind to a human protease. Research teams in Germany have been able to crystallize the protease and have used this structure to optimize an existing α-ketoamide inhibitor developed to combat other diseases.

Figure 5SARS-CoV-2 coronavirus protease dimer bound to an α-ketoamide inhibitor (yellow). The image is reproduced from C&EN news.


20 March 2020: SwissProt has modeled the full SARS-CoV-2 proteome based on the NCBI reference sequence NC_045512 which is identical to GenBank entry MN908947, and annotations from UniProt. All data is deposited here.


20 March 2020: Check out refined coordinates of existing experimental SARS-CoV-2 structures using ISOLDE by Tristan Croll (Cambridge University). Modeled coordinates are deposited here.

20 March 2020: Prediction of 10 models for SARS-CoV-2 proteins from the Feig lab.


17 March 2020: The first vaccine clinical trial against SARS-CoV-2 starts in Seattle by Moderna in collaboration with NIAID. The experimental vaccine contains synthetic m-RNA clones that encode glycoprotein S. Once human cells recognize the genetic material of the virus, it is hoped that they will produce antibodies that inactivate the viral glycoprotein S. This strategy is different from the Influenza vaccine, where the viral surface protein itself, hemagglutinin, is introduced into the body and the human immune system produces antibodies against that protein.


5 March 2020: Check out computational predictions of protein structures associated with COVID-19 by DeepMind using AlphaFold, their recently published deep learning system, focuses on predicting protein structure accurately when no structures of similar proteins are available, called “free modelling”.


3 March 2020: Researchers at the Structural Genomic Infectious Diseases Center resolve the crystal structure of SARS-CoV-2 Nsp15 / NendoU endoribonuclease in high resolution. (PDB IDs: 6W01, 6VWW).


20 February 2020: A third research team also published the structure of the SARS-CoV-2 glycoprotein S of SARS-CoV-2 in two conformations using cryo-electron microscopy. (PDB IDs:6VXX, 6VYB)


19 February 2020: A research team from China presents cryo-EM structures of the SARS-CoV-2 glycoprotein S bound to the human ACE2 receptor. The structure shows the full-length human ACE2, in the presence of a neutral amino acid transporter B0AT1, with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resolution of 2.9 Å, with a local resolution of 3.5 Å at the ACE2-RBD interface (PDB IDs: 6M18, 6M1D, 6M17).Figure3Overall structure of the RBD-ACE2-B0AT1 complex. The complex is colored by subunit, with the ACE2 protease (PD) region depicted in cyan and the Collectrin-like region (CLD) of ACE2 in blue. The glycosylated parts of the human ACE2 receptor are illustrated in strick representation. The RBD subunit of the structure of glycoprotein S that binds to ACE2 is depicted in yellow. The figure has been adapted from the original publication.

15 February 2020: The first cryo-EM structure of the viral spike protein (glycoprotein S) is published at a resolution of 3.5 Å (PDB code: 6VSB). Based on the SARS-CoV-2 genome sequence shared by Chinese researchers, they managed to prepare a purified sample of the spike protein and to determine its structure using single particle cryo-EM in less than two weeks. Using surface plasmon resonance they also measured that SARS-CoV-2 glycoprotein S binds 10-20 times more to the human cell ACE2 receptor than the 2002 SARS-CoV virus glycoprotein S. Figure2The structure of the glycoprotein S of SARS-CoV-2, as identified by cryo-electron microscopy. Green binds to the binding site that binds to human cells. In the middle image, the green binding domain of glycoprotein S is positioned for binding to the human enzyme ACE2. On the right is the SARS-CoV glycoprotein S for comparison. The figure has been adapted from the original publication.

5 February 2020: The crystal structure of the SARS-CoV-2 main protease is released in the PDB (PDB ID: 6LU7).

3 February 2020: The complete viral genome of the new coronavirus was analyzed by scientists in China.

30 January 2020: The World Health Organization has named the new virus SARS-CoV-2 and the disease caused by the new virus, COVID-19, and the outbreak was declared a Public Health Emergency of International Concern.

5 January 2020: The source of this infection was quickly identified as a new coronavirus that resembles those that caused SARS-CoV outbreaks in 2002-2004 and MERS-CoV in 2012, but is not the same virus.

31 December 2019: A pneumonia of unknown cause detected in Wuhan, China was first reported to the WHO Country Office in China on 31 December 2019.

366 Days: The Year in Science

Read below the Science Review of 2012 by Nature Magazine, with Greece making it to the top 22 “leading science nations” with 1% of the ‘most cited papers’!


Higgs boson: Proton-proton collisions as measured by Cern

Also, read on Science Magazine’s Breakthrough of the Year 2012 (Higgs Boson) and the runners-up: Genome Engineering, Curiosity Landing, Bionics, Eggs from Stem Cells, Encode, X-ray laser advances and more!



Industry and academia tie the knot

When I was a student at the University of Athens in the late 90s, receiving funding from the Industry was almost unheard of. Although I was an undergrad at the time, I could see that the general Greek academic perception of collaborating with the Industry was viewed almost as the equivalent of a sell-out. Researchers considered teaming up with the Industry the betrayal of their academic purity.

When I was a student at the University of Heidelberg in Germany, things were different: A fair number of the lab’s grants stemmed from the Industry: the Volkswagen Foundation, BASF, Novartis, etc. and that was seen as an achievement. Our lab was not the only one to work with the Industry. It was a very common theme for Principal Investigators (PIs) in Germany to reach out to the Industry and big pharma, partner up, and exploit the best of both worlds.

When I was at Yale University, the situation was even better: It was now the Industry who reached out to us researchers. I was very fortunate to serve as the co-President of a very successful student society, the Yale Biotechnology and Pharmaceutical Society (YBPS), now called Yale Healthcare and Life Sciences Club (YHLC). Industry sponsored our events and seminars, such as the “Life Sciences Case Competition”, the “Business of Biotechnology Seminar Series”, the “Healthcare Conference” and many others, in order to interact with us and possibly recruit students or form collaborations with research groups of the University.

When I arrived at the Biomedical Research Foundation of the Academy of Athens in October 2009 as a faculty member, a pleasant surprise was awaiting me: The Greek General Secretariat for Research and Technology (GSRT) had just announced a grant call, named “Synergasia” (“Cooperation” in English), which aimed to enhance the ties and cultivate the collaboration between Greek Industry and Academia.

So times are changing. There is a new mindset in the academic world (at the very least in my area of expertise, drug discovery). Recent articles such as Nature’s Scibx, “Small (molecule) thinking in academia”, and “Partnering between pharma peers on the rise” of Nature Reviews Drug Discovery, explain how and why pharmaceutical–academia deals, such as the $100-million Pfizer pact with 8 academic Institutions from the Boston area, have been stealing headlines this year. In another recent brief mention in Nature, faculty members say that industry research has contributed to important work.

Life-science researchers in US universities receive $33,000 a year on average from the medical drug and device industry. […] More than half (51.9%) said they maintain a relationship with industry. The study found that such relationships provide significant benefits both to the researcher and to science. Among faculty members most involved with industry research, nearly half said it “contributed to their most important scientific work and led to research that would not otherwise have been possible”.

Exciting times. Still, challenges and caveats are obviously not absent. True collaborative environment between the partners, licensing/IP and publishing issues, technology transfer know-how, commercialization matters and different goals for each institution, are all issues that need to be seriously considered before teaming up in such consortia.

Graphene, the strongest material on earth, now produced from cookies, roaches and dog feces

Graphene is a material made of carbon. It is a particularly interesting material because in graphene, carbon manages to arrange itself in a sheet just one atom thick (see pic on the left). The material is so thin, that three million sheets of graphene on top of each other would be just 1mm thick. This one-atom thick sheet, densely packed in a honeycomb lattice, has excellent electrical, mechanical and thermal properties that make it the strongest material on earth, an improvement upon and a possible replacement for silicon, and the most conductive material known to man.

In 2004, physicists at the University of Manchester and the Institute for Microelectronics Technology, Chernogolovka, Russia, first isolated individual graphene planes by exfoliating graphite (i.e. the material used for pencils) using adhesive tape. Since 2009 it has been described as the strongest material on earth, 200 times stronger than steel. In 2010, the Nobel Prize in Physics was awarded to Andre Geim and Konstantin Novoselov, “for groundbreaking experiments regarding the two-dimensional material graphene”.

It would take an elephant, balanced on a pencil, to break through a sheet of graphene the thickness of Saran Wrap.

See through: Researchers have created a flexible graphene sheet with silver electrodes printed on it (top) that can be used as a touch screen when connected to control software on a computer (bottom). Credit: Byung Hee Hong, SKKU.

said Professor James Hone of Columbia University in a statement.

As for uses? It can be used for making up new materials and electronic devices. Sort of like plastics are used nowadays but with an extra touch of technology. It could be used for transparent electronics that are stronger, cheaper, and more flexible such as shown on the right. Professor Tour of Rice University said teasingly:

You could theoretically roll up your iPhone and stick it behind your ear like a pencil.

Graphene is usually made up from graphite. But as the demand for cheap and fast large-scale graphene production becomes imminent, it quickly became clear that making graphene by splitting graphite crystals using adhesive tape, had no future.

Now a team of researchers led by Prof Tour, managed at to grow graphene directly on the backside of a copper foil at 1050°C, using six easily obtained, low or negatively valued raw carbon-containing materials used without pre-purification (cookies, chocolate, grass, plastics, roaches, and dog feces). Read the full paper here. Thanks to Anastassia for the story!

Worst comes to worst you just might end up using up that pizza from last night to get a new rollable iPhone. And think twice before you scold your dog again for doing a #2 on the carpet!

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