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Report

International School of Crystallography

47th Course – Structural Basis of Pharmacology: Deeper Understanding of Drug Discovery through Crystallography

30 May to 8 June, 2014

 

This Course was held in Erice, Italy at the Ettore Majorana Foundation and Centre for Scientific Culture. As was the case for all the past editions, the event was publicized by mailing about 8000 announcements world-wide about one year ahead of the course. Over 250 applications were received and the large number as well as the outstanding quality of the applications made this process quite difficult, but at the end approximately 120 students were accepted for the Course (28 nations were represented). Participants were largely from university (Ph.D. students, postdoctoral and young researchers), with some members of chemical and pharmaceutical companies.

The schedule for a typical day included a morning session, with four 45-minute lectures, followed by a lunch break. The afternoon session usually started with two lectures, followed by different types of tutorials.

The program of the Course was designed to show how structure-based drug design can be used to discover and optimize inhibitors as small molecule drugs as well as to target protein-ligand and protein-protein interactions and how structural knowledge is nowadays applicable to all aspects of drug discovery, from lead identification and lead optimization, to ADMET prediction, and drug repurposing.

Approximately half of the lecturers were from pharmaceutical companies or had significant experience in founding biotechnology and biopharmaceutical companies. This expertise complemented the extremely high level of academic lecturers, who represented the many branches of science required to meet the challenges of the highly diverse challenges encountered in drug design. The blend of academic-pharmaceutical science recognizes the reality that drug design emanating from non-pharmaceutical company efforts requires cooperation with the commercial sector for any likelihood of success.

Different topics were covered by the lectures, which include:
- Complex systems and drug design (membrane proteins, epigenetic targets, ribosomes, and biologics) with talks designed to explain how the different requirements for stability and crystallization of these systems are addressed;
- Protein-protein interactions, with focus on aspects of cell regulation and signaling, and how, being able to regulate these processes with small molecules, may allow for the development of novel therapeutic treatments;
- The small molecule universe, with discussions about how small molecules (ligands) structures may impact drug discovery in ways sometimes not fully understood or appreciated. The use of the wealth of structural information available in the CCDC repository and the application of concepts such as molecular geometry, conformation, and flexibility to drug design were also discussed;
- Protein states and protein-ligand interactions: several talks addressed the importance of understanding the characteristics of protein-protein and protein-ligand interactions to optimize the drug design process. The ever-increasing importance of the role of the PDB as the worldwide repository for protein and other macromolecular structures was also discussed at a time when the number of experimental structural entries from X-ray and NMR has recently surpassed 100,000;
- Structural data quality: the importance of having high quality protein and protein-ligand X-ray structures was also highlighted, and the methodology necessary to search through the available data, verify and improve on structure quality was also presented;
- Ligand docking and fragment-based drug discovery: these approaches to lead identification were presented in several talks, and fully discussed in two plenary lectures, which highlighted the problems and successes associated with the technique;
- Lastly, the enhancing resolution of cryo-electron micrographic structures and how they can affect drug discovery were also discussed.

Ten participants were selected from the submitted abstract to give an oral presentation during the Course:
- Hanna Kyle presented her work on Biophysical and structure characterization on Protein-protein interaction to enable drug design;
- John Darby talked about the results of fragment screening to reveal novel activators of certain enzyme;
- Nicolas Levy reported on the HIV-1 pre-integration complexes;
- Stefano Stella presented new tools for precise genome editing;
- Jens Carlsson exposed the ligand discovery from GPCR crystal structure and homology models;
- Pavel Plevka reported on his recent results on Saffold virus;
- Nedyalka Radeva explained how to design novel inhibitors from fragments exploiting dynamic combinatorial chemistry;
- Luigi De Colibus talked about a new generation of potent virus inhibitors resulting from structure based analysis;
- Laura Preiss discussed about the target of a novel TB drugs;
- Irina Prokhorova showed her work the structural basis for the inhibition of the eukaryotic ribosome.

Awards and participant Feedback

During the closing ceremony, several awards were presented. Due to the large numbers of posters, two different categories of awards were assigned (based on the number assigned to the poster, odd or even): the first places were assigned to Mirella Vivoli ( University of Exeter, UK) and Taiana Oliveira (EMBL-Grenoble, France); William Fernandes (University of Sao Paulo, Brazil) and Ulrike Krug (University of Leipzig, Germany) were awarded of the the second places and the third ones were conferred to Robert Gustafsson (Stockholm University, Sweden) and Marc Fiedler (Laboratory of Molecular Laboratory, Cambridge, UK). Due to the excellent quality of the presentation, the committee awarded also two prizes as special mention to Disha Patel (Rutgers University, NJ, USA) and to Alessio Ciulli (University of Dundee, Ireland).

The Lodovico Prize (acknowledging the most active student inside and outside the lecture hall) was given to Anthony Bradley (University of Oxford, UK). Below a picture of the prize winners.

At the end of the Course, participants were asked to participate to a survey to judge and comment on the quality of the Course. Their responses indicates that a similar meeting should be held at least in 4 year time and that the course have been successful in most of its objectives (score 91/100) .

2014 was a very special edition of the School: this was the year of the 40th anniversary of the School and we celebrated it with a game (Game of the Goose, Gioco dell'Oca in Italian) in which 6 different teams, composed each by ten young participants, had to answer questions about different subjects (Sicilian history, crystallography, Sicilian cooking and so on) in order to complete the race course and win the prize.

Later in the evening we celebrated the International Year of Crystallography with a Bal en Tête: participants were asked to bring red hats with a crystallographic subject. Everyone agreed enthusiastically to the request, to the point that the committee in charge of the selection had a hard time to identify the winners.

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From left to right: Disha Patel, Robert Gustafsson, Marc Fiedler, William Fernandes, Mirella Vivoli, Anthony Bradley, Taiana Oliveira, Paola Spadon, Giovanna Scapin, and Annalisa Guerri.