Monday, 17th September, 2012

Multiscale simulation in the prediction of drug-induced cardiotoxicity: Integrating molecular, cellular and tissular levels

VPH 2012 Conference, London, UK, 18-20 September 2012

Speaker: Obiol-Pardo C, Gomis-Tena J, Sanz F, Saiz J, Pastor M

Saturday, 1st September, 2012

Development of an integrated in silico prediction system of drug toxicity endpoints

International Symposium on Medicinal Chemistry, Berlin, Germany. 2-6 September 2012

Speaker: Carrió P, Cases M, Sanz F, Pastor M

Thursday, 12th July, 2012, 11:00-12:00

Multitarget strategies in the search of novel drug candidates for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is a disruptive brain disorder characterized by a massive neuronal loss leading

to a progressive decline of cognitive function. The cause of AD is poorly understood. Several hypotheses have been proposed over the years to explain the disease and to identify relevant drug targets. It has been shown that AD is always associated with the formation of plaques (amyloid hypothesis) as well as with the deposition of neurofibrillary tangles (tau hypothesis).
There are few currently approved drugs, and these offer just a small benefit for a relatively short period of time. Nowadays, AD represents the largest unmet medical need in neurology.
Our approach to drug discovery in AD has been based on a radical change of the classical ‘one-drug one-target’ paradigm into a multitarget drug discovery approach. In this seminar, two different series of molecules discovered following the multitarget strategy will be presented. The initial steps of our drug discovery strategy will be discussed, from structure-based drug design, carried out by means of computational tools, to chemical syntheses, and in vitro and in vivo characterization.

Speaker: Dr. Andrea Cavalli, Italian Institute of Technology (IIT), Genova, Italy

Room Xipre (seminar 173.06-183.01)

Monday, 4th June, 2012

Molecular recognition by simulations

2nd Aegean Conference on Molecular Recognition, Rodos Palace Conference Center, Ixia, Rhodes, Greece, 5-10 June 2012.

Speaker: Gianni de Fabritiis

Thursday, 31th May, 2012, 11:00-12:00

Ongoing Adventures in Fragment Based Drug Discovery

The use of weak binding “fragments” of molecules is now recognised as an efficient and robust method of hit identification in the drug discovery process. The use and integration of fragment hits into successful lead optimisation is the critical determinant of whether this technology will become accepted as a significant tool in drug discovery. A number of compounds which have evolved using fragment based hit identification are now in phase I-III clinical trials suggesting that this is a technology which will find a permanent place in the armory of the Drug Discovery Scientist. At the newly established Drug Discovery Programme at the Beatson Institute for Cancer Research we are exploiting the basic biology strengths within the Beatson Institute and wider Cancer Research UK network, to investigate some of the most exciting and challenging cancer targets. Central to our strategy is Fragment-Based Drug Discovery methods and we will use NMR and Surface Plasmon Resonance as primary tools for fragment-based hit identification. I will discuss some results around our initial forays into some of these areas.

Speaker: Dr. Martin Drysdale, Drug Discovery Programme, Beatson Institute for Cancer Research, Glasgow, UK

Room Charles Darwin seminar

Tuesday, 29th May, 2012

eTOX – Data integration for in silico toxicity prediction.

IMI Stakeholder Forum 2012, Brussels, Belgium, 30 May 2012

Speaker: Sanz F

Sunday, 20th May, 2012

Fragment-based drug design using molecular dynamics,

2012 Workshop on Free Energy Methods in Drug Design, May 21-23, Cambridge, Massachusetts, USA.

Speaker: Gianni de Fabritiis

Thursday, 17th May, 2012, 11:00-12:00

Elucidating Structural and Folding Dynamics of Proteins by Simulations

All-atom molecular dynamics simulations provide a vehicle for capturing the structures, motions, and interactions of biological macromolecules in full atomic detail. Such simulations have, however,
been limited both in the timescales they could access and in the accuracy of computational models used in the simulations. I will begin by presenting briefly how progress has been made in both of these areas so that it is now possible to access the millisecond timescale, and how we have been able to parameterize relatively accurate energy functions. I will then present recent results that highlight how such long-timescale simulations have been used to provide insight in to protein dynamics. In the area of protein folding, we have used simulations to describe the general principles of how fast-folding proteins fold. In simulations of 12 structurally diverse proteins, representing all three major structural classes, we observe the proteins to spontaneously and repeatedly folded to their experimentally determined native structures. I will present the results of the analyses we performed to identify the common principles that underlie the folding of these proteins. I will also describe how simulations can be used to describe slow motions present in proteins, in both folded and unfolded states.

Speaker: Dr. Kresten Lindorff-Larsen, University of Copenhagen, Denmark

Room Xipre (seminar 173.06-183.01)

Thursday, 26th April, 2012, 11:00-12:00

Complementary tools in structural Biology at the European synchrotron

Speaker: Philippe Carpentier, Structural Biology, European Synchrotron Radiation Facility, Grenoble, France

Room Xipre (seminar 173.06-183.01)

Tuesday, 24th April, 2012, 11:00-12:00

De-Novo Discovery of Differentially Abundant DNA Binding Sites Including Their Positional Preference

The identification of DNA binding sites has been a challenge since the early days of computational biology, and its importance has been increasing with the development of new experimental techniques and the ensuing flood of large-scale genomics and epigenomics data yielding approximate regions of binding. Many binding sites have a pronounced positional preference in their target regions, which makes them hard to find as this preference is typically unknown, and many of them are weak and cannot be found from target regions alone but only by comparison with carefully selected control sets. Several de-novo motif discovery programs have been developed that can either learn positional preferences from target regions or differentially abundant motifs in target versus control regions, but the combination of both ideas has been neglected. Here, we introduce Dispom, a de-novo motif discovery program for learning differentially abundant motifs and their positional preferences simultaneously. Dispom outperforms existing programs based on benchmark data and succeeded in detecting a novel auxin-responsive element (ARE) substantially more auxin-specific than the canonical ARE.

Since its publication, we have endowed Dispom with more complex motif models and extended it to handle weighted input data such as ChIP-seq or BS-seq data. We have been applying Dispom to in-house and publicly available data of different transcription factors and insulators in yeasts, plants, and mammals as well as to protein-binding microarrays, where it turned out to be one of the top-scoring approaches in the corresponding DREAM challenge.

Speaker: Dr. Ivo Grosse, Institute of Computer Science, Martin Luther University, Halle, Germany

Room Xipre (seminar 173.06-183.01)