Tag Archive | pharmacology

“We’re evolving towards systems pharmacology”

 

Jordi Mestres in the lab

A theoretical chemist by training, Jordi Mestres started up the chemogenomics lab of the IMIM, currently part of the GRIB, in 2003. The structure of the group, made up of graduates and doctors in chemistry, biology, biotechnology and computer science, perfectly reflects its three main lines of research: molecules, proteins and programming to predict the interaction between them.

“We apply our predictions to both drug discovery and chemical biology”, summarises Mestres. This last discipline consists of using small molecules to sound out biology, for example inhibiting a protein to understand its function. According to the scientist from Girona the optimisation of these chemical probes is just as important as that for drugs. “They have been used for years as if they were selective for a single target protein, but now we are beginning to understand that they are not.”

In fact, drugs do not owe their effectiveness to the fact that they are very selective for a single target, rather to their affinity for a whole group of proteins. “We are evolving towards systems pharmacology, where the drug is placed in the context of all of the proteins with which it can potentially interact, the organs it can reach, the polymorphisms of the person that takes the drug, and so on”, explains the head of the group.

 

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 A multitude of projects

The laboratory is involved in several European projects, including Open PHACTS, where they have developed an interactive tool to show ligand-protein interactions via the web (www.pharmatrek.org), and eTOX coordinated by Ferran Sanz (GRIB), where they design new methods to predict drug safety profiles. “Drug safety profiles are not really known until they are on sale and the drug is exposed to millions of users. If we were able to anticipate any adverse effects before entering the market and we understood the mechanisms, we could modify the structure of the drug in advance”, reasons Mestres.

They also look at ethnopharmacology, and try to explain how medicinal plants work. “We have made predictions for 109 plants and we are trying to rationalise their use for cardiovascular disease.”

In collaboration with Pilar Navarro (IMIM) they have found molecules inhibiting the formation of b-amyloid plaques that work as well or better than memantine, an Alzheimer’s drug. The research was funded by a pharmaceutical company and has generated two patents. In total, the group has four patents in collaboration with companies and one with the CSIC.

The creation of a spin-off

In some cases, they are asked by companies or other groups to prioritise which molecules to use at the beginning of a research project or to predict the proteins of active molecules in phenotypic trials. This was the origin of Chemotargets, in 2006, where currently three people work. “The students who were doing this could not publish anything, so we created this spin-off service”, explains the head of the group.

Chemotargets is still going and has quite a lot of work. They are currently designing the screening collection for the Karolinska Institute in Stockholm, with more than 10,000 molecules. They did something similar for the CRG, creating a list of small molecules that interact with proteins of interest to the researchers. Lately, they have also been contracted by the Swiss foundation ‘Medicines for Malaria Venture’ (MMV) to investigate the action of 400 antimalarials identified in phenotypic tests. “Chemotargets predicts targets for each molecule. Afterwards it is necessary to confirm the predictions experimentally, and this work is usually outsourced”.

It is, according to Mestres, the future of drug design. “Everything will be done from an office in a skyscraper in Manhattan or London, outsourcing molecule design to companies like Chemotargets, synthesis to a chemical company in China, and the trial to a pharmacology firm in India”, he predicts. “In fact it is already happening with the big pharmaceutical companies -they close their research centres, but do not abandon projects: they subcontract them out”.

 

“We are the interface between industry and academia” – Computer-assisted drug design lab

The Computer-Assisted Drug Design (CADD) laboratory of the GRIB is devoted to the area of drug design and development. Directed by Manuel Pastor, who started the group 10 years ago at the IMIM, it includes pharmacists, biologists, chemists, and a mathematician. “We also had a telecommunications engineer at one point. Our research needs experts in both science and programming”, justifies Pastor.

The group’s interests are divided into three main areas. The first is methodological: they have written several programs marketed and are used by many pharmaceutical companies. The most recent one is Pentacle, which allows the creation of models relating the structure with the activity of a compound, as well as the computation of molecular descriptors. “Molecular descriptors are used to convert a real molecule into a computer representation, so they are needed in pretty much all steps of drug development”, explains the head of the group. Another software tool created by the group a few years ago is Shop. “Imagine you have a molecule that has the desired effect, but it cannot be used: because, for example, it’s toxic, or not soluble enough. With Shop you can remove the fragment that causes the problem and substitute it for another that will maintain the same biological activity without the side effect”.

A second research area is structure-based drug design (SBDD), which they apply to the study of schizophrenia. In collaboration with other groups in Santiago de Compostela they are looking at potential drug targets for the disease to try to find new compounds that can bind them.

Innovating Medicines 

The most recent and active research area is focused on drug safety. The group coordinates the IMI (Innovative Medicines Initiative) project eTOX, which aims to develop methodologies to predict toxic properties of new compounds in silico (with the help of computers) and as early as possible. “This project involves pretty much all the big pharmaceutical companies in Europe, as well as some of the best European academic groups in cheminformatics”- says Pastor – “Pharma companies have realised that what is making it difficult for them is not the competition, but the intrinsic complexity of the problem. They have run out of easy targets, and the existing methodologies are not working that well finding good drugs for the difficult ones. So they are starting to join forces”.

Another upcoming IMI project Pastor is excited about is OpenPhacts (Open Pharmacological Space). As with eTox, Pastor will collaborate with Ferran Sanz and other GRIB members, to contribute to this project which “will change the scene completely”, promises the head of CADD. “There is a lot of information publically available information that is of interest to pharmaceutical companies: data on compounds, structures and, pathways. But it’´s all dispersed, and the industry is spending huge amounts of money trying to collect and exploit this information. OpenPhacts will bring together make pertinent enquiries, such as: is there a compound similar to this one involved in this specific pathway? The CADD group will contribute by assessing these relevant questions. “The drug companies know what they need, and the technical experts know what can be done. We are the intermediaries, we know about both worlds”, concludes Pastor.

This article was published in the El·lipse publication of the PRBB.

Neuropharmacology Research Unit (CEXS-UPF)

Drug abuse and emotional disorders, such as anxiety and depression, are generating a serious social problem. This is why Rafael Maldonado’s neuropharmacology group at the CEXS-UPF studies the common biological mechanisms involved in these two phenomena. They focus particularly in nicotine, cannabis, cocaine and ecstasy, and in the possible mechanisms underlying the abusive consume of these substances.

Maldonado explains there are three factors to understand why some people become addictive and others don’t: drug consume (the quantity, the frequency, the mode); social and environmental factors; and individual vulnerability, which includes genetic factors. A classical example of the effect of the environment is how the American marines that were heroin addicts in Vietnam quitted easily once back at home.

In order to understand addiction and emotional disorders, the group, formed by 29 people, uses different techniques: classical pharmacological strategies, using compounds that act on the nervous system receptors; ‘knock-out’ mice in which a specific gene has been deleted in order to understand its function; and animal models for behaviour studies which, according to Maldonado, are very complex but once they are established they allow a good prediction of what can happen in humans.

Maldonado highlights the discovery that specific components of the endogenous opioid system are a common substrate for different addictive behaviours as a major contribution of his group. His dream: that this knowledge gives rise to effective treatments for the addicts, who are people with a chronic disease, emphasizes the researcher.

This article was published in the El·lipse publication of the PRBB.

Overexpressing the Nicotinic acetylcholine receptors in mice increases sensitivity to nicotine

A publication in Amino Acids by researchers from UPF, CRG and other centers provides the first in vivo evidence of the involvement of the CHRNA5/A3/B4 gene cluster in nicotine addiction. It happens through modifying the activity of brain regions responsible for the balance between the rewarding and the aversive properties of this drug. CHRNA5/A3/B4 codes for the nicotinic acetylcholine receptor subunits A5, A3 and B4. Together they form the ligand-gated pentameric ion channels that modulate key physiological processes ranging from neurotransmission to cancer signaling. These receptors are activated by the neurotransmitter, acetylcholine, and the tobacco alkaloid, nicotine. Recently, the gene cluster received interest after a succession of linkage analyses and association studies identified multiple single-nucleotide polymorphisms in these genes that are associated with an increased risk for nicotine dependence and lung cancer.

To see the in vivo effects of the cluster, a transgenic mouse overexpressing the human CHRNA5/A3/B4 cluster was generated using a bacterial artificial chromosome. Transgenic mice showed increased functional receptors in brain regions where these subunits are highly expressed under normal physiological conditions. Moreover, they exhibited increased sensitivity to the pharmacological effects of nicotine. Transgenic mice also showed increased acquisition of nicotine self-administration.

Reference:
Gallego X, Molas S, Amador-Arjona A, Marks MJ, Robles N, Murtra P, Armengol L, Fernández-Montes RD, Gratacòs M, Pumarola M, Cabrera R, Maldonado R, Sabrià J, Estivill X, Dierssen M. Overexpression of the CHRNA5/A3/B4 genomic cluster in mice increases the sensitivity to nicotine and modifies its reinforcing effects. Amino Acids. 2011 Nov 19

 

 

© 2010 Oncogene: Structure of the Nicotinic acetylcholine receptor (nAChR). (a) Schematic representation illustrating the pentameric arrangement of subunits in an assembled nAChR. (b) Conserved domains of a nAChR subunit including the amino (N) and carboxy (C) terminals, transmembrane segments (M1–M4) and the intracellular loop. (c) Assembly of heteromeric and homomeric nAChR subtypes. Individual nAChR subunits are represented as colored circles, with diamonds representing ligand-binding sites. Pentagons in the center of each pentamer represent the pore region.

The effect of genes and environment on the consequences of ecstasy use

The Human Pharmacology and Clinical Neurosciences group of the IMIM-Hospital del Mar, lead by Rafael de la Torre, has published a paper in PLoS One  this week to try to clarify the association between cumulative use of MDMA (ecstasy), one of the most popular illegal psychostimulants abused among youth,  and cognitive dysfunction. They have also set to understand the potential role of candidate genetic polymorphisms in explaining individual differences in the cognitive effects of MDMA.

Several studies have suggested that MDMA induces neurotoxicity, which primarily affects the serotonin system and is linked to memory dysfunction. There is also evidence that several gene polymorphisms may contribute to explain variations in the cognitive impact of MDMA across regular users of this drug.

The research group took 60 ecstasy polydrug users, 110 cannabis users and 93 non-drug users and assessed them using several cognitive measures. Participants were also genotyped for polymorphisms within six genes. The scientists  found that both MDMA lifetime use and gene-related individual differences influence cognitive dysfunction in ecstasy users.

According to the authors  “this study reliably demonstrates dose-related effects of MDMA use on visual attention, organization and memory”.

Reference:
Cuyàs E, Verdejo-García A, Fagundo AB, Khymenets O, Rodríguez J, Cuenca A, de Sola Llopis S, Langohr K, Peña-Casanova J, Torrens M, Martín-Santos R, Farré M, de la Torre R. The Influence of Genetic and Environmental Factors among MDMA Users in Cognitive Performance. PLoS One. 2011;6(11):e27206 [PDF]

“Habitual competitors are now working together to get better toxicity predictions”

Ferran Sanz (IMIM-UPF) tells us about the eTOX project in a recent interview published in El·lipse, the monthly PRBB publication.


The electronic toxicology project (eTOX) started in January 2010 as one of the projects funded in the first call of the IMI (Innovative Medicines Initiative), a unique public-private partnership between the European Community and the European Federation of Pharmaceutical Industries and Associations (EFPIA). Ferran Sanz, director of the Research Programme on Biomedical Informatics (GRIB, IMIM-UPF) and academic coordinator of eTOX, evaluates the project’s achievements so far as very positive.

What exactly is eTOX about?
All IMI projects, including eTOX, bring together European pharmaceutical companies and academic groups to address scientific challenges that are a priority for the pharmaceutical industry. In the case of eTOX, the aim is to facilitate the early prediction of drug toxicity through computational models. It will last a total of five years.

How is that done?
The first step is an intensive data collection exercise in which structural and toxicological information on tested compounds is gathered from the archives of the participating pharmaceutical companies. This is the first time they have agreed to share such sensitive information, originating from animal experiments. On the basis of this shared information, computer models can be created to allow better in silico prediction of toxicology for newly designed drugs. The future perspective is to be able to develop new drugs more efficiently, with less toxicity and in a shorter time period. This procedure will not only reduce the costs of drug development, but also the amount of animal experimentation.

Who are the participating partners?
Out of the 25 partners from different European countries, 13 are pharmaceutical companies, five small and medium-sized enterprises, and seven academic institutions. Originally there were 11 pharmaceutical companies, but two more asked to collaborate and contribute after the project had started. The fact that the participation of the companies implies a substantial financial and manpower contribution from their part without receiving any public funding, indicates their interest in the topic.

What were the achievements in this first one and a half year of the project?
In the first year the highlight has been the positive attitudes of all of the partners, which result in the consolidation of a very productive teamwork. Even though some partners are usually competitors searching for new pharmacological targets and drugs, within the eTOX project they collaborate enthusiastically to achieve a common goal: to find a solution to avoid toxicity and develop safer new drugs.

We have already created the database for the shared information and procedures for semiautomatic data extraction from the toxicology reports. We have also defined the computational architecture of the predictive system and we have already developed the first modules of such system.

What steps will be taken in the future?
Once the database infrastructure has been set up, it is being fed with the information extracted by the archives of the pharmaceutical companies. On the basis of the data accumulated in the database in each moment, the predictive system is being progressively trained. Then, it will be tested within each company with internal data not included in the eTOX database. According to the incremental experience and emerging problems, the system will be improved and further developed.

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