Relevance of the project

The project entitled: DEVELOPMENT OF A BIOINFORMATIC QSAR SYSTEM FOR ANTITUMORAL AND ANTIRHEUMATIC DRUG SUBSTANCES MODELLING IN INDIVIDUALIZED THERAPIES (BIOINFOQSAR) has as principal objective designing, development and implementation of a modern and innovative technology for cancer and for autoimmune diseases with inflammatory component therapy approach, as complex health care problem.

The project focuses on the creation of a bioinformatic framework for application of the modern principles of molecular medicine combined with personalized medicine and individual therapies, which could further be generalized and applied for studies in any therapeutic areas of research. Within the simulative proposed consortium that include well-known and recognized universities, a famous national research institute and a small, medium-sized enterprise from the private research area, BIOINFOQSAR will pipeline by it’s development to the competitiveness enlargement of the research, development and innovation activities on the national plan level, in priority domains as Health and Biotechnologies.

BIOINFOQSAR specifically addresses the part of the 4th Program call listed under 6th Research Direction: Biotechnology, 6.1 Biotechnology, 6.1.5 Research and development of the bioinformatic systems for cellular activity and information processing mechanisms at biologic level, including cognitive level modelling and monitoring. BIOINFOQSAR also great implication to the part of the call listed under 4th Research Direction: 4.1 Health, 4.1.4 Development of the modern therapies guided to the chemical, genetic and cellular support and its bioethical norms standardization.

The main goal of the project is to deliver a unitary and specialized bioinformatic system for molecular modelling - in silico drug design, using Quantitative Structure-Activity Relationships, QSAR models for predicting pharmacological activity and coupling the predicting technologies with in vitro tests (developed on neoplasic transformed cellular lines and on normal human cells and also on enzymatic purified systems). By mean of QSAR principles completed with QSPR (Quantitative Structure-Property Relationships), shall be developed an optimized, efficient and robust base for antitumoral and antirheumatic activity prediction in large classes of conventional anticancer drugs, focusing on a priority and challenging area of individualized therapy and personalized medicine.

Under the European Commission’s proposal for new legislation relating to the registration of new and existing chemical substances ( it is foreseen that QSARs will be used more extensively. Recent policy developments in the European Union (EU) and within the Organization for Economic Cooperation and Development (OECD) have placed increased emphasis on the use of structure-activity relationships (SARs) and quantitative structure-activity relationships (QSARs), collectively referred to as (Q) SARs, within various regulatory programs for the assessment of chemicals and products, which calls for an increased use of (Q) SARs and other non-animal methods, especially for the assessment of low production volume chemicals.

The project BIOINFOQSAR is completely integrated to the theme Health from the FP7 April call, with the principal objective the improving the health of European citizens and increasing the competitiveness and boosting the innovative capacity of European health-related industries and businesses, while addressing global health issues. The aim of the proposed project directly related to the European policy context and FP7 Health theme in order to advance our understanding on how to more efficiently promote good health, to prevent and treat major diseases and the emphasis will be put on translational research (translation of basic discoveries into clinical applications including scientific validation of experimental results), the development and validation of new therapies.

The project specifically are relating with the FP7 Cooperation Work Program Topic HEALTH-2007-1.3-3: PREDICTING SUITABILITY, SAFETY AND EFFICACY OF THERAPIES, with the guiding line: Promotion, development, validation, acceptance and implementation of QSARs (quantitative structure-activity relationship), and which includes developing tools to explore the full range of phenotypic responses of biological systems to chemicals, in order to create a robust basis for predictive capabilities. The theme of BIOINFOQSAR will also contribute to the development of alternatives to animal testing in biomedical research in line with the "The Three R’s principle ( Replacement, Reduction and Refinement) of animal testing.

In these area of interest, the project proposal are going to contribute: to express and quantify the variability in therapeutic response of the antitumoral and anti-inflammatory drug substances in highly predictive QSAR models (immunological status, genetic heritage, etc., as function of pharmacological activity and molecular structure), to verify the predicted values with in vitro tests on cellular models, and even more ambitious goal: to serve to the clinicians in personalized medicine drugs prescription.

Major premises and novelty elements of the project proposal

Molecular modelling, molecular engineering and bioinformatics are the central items of the project, all of them in the view of personalized medicine (the science of being able to match specific patients to specific therapy that is still in its infancy). It was conceived to exploit the power of Virtual Computing Medicine and highly predictive and discriminated QSAR/QSPR models as a solution for identification of predictive biomarkers, responsible for individualized response to the drugs. The resources of this project will be exerted to identify these structural descriptors that will truly allow the tailoring of therapeutic regiments to the individual patient. For this “long-term” goal, the BIOINFOQSAR project will develop an unitary framework of knowledge discovery: an original, specialized software, created for QSAR analysis and modelling discriminate functions of correlation antitumoral and antirheumatic activity with the structural descriptors that can effectively predict the targeted property.

Another major premise and novelty element include the construction of a QSARs Models Digital Library by means of great applicability and implementation of the specialized and original software. This digital library could be the motor force for further starting points of drug discovery research studies. The most sobering fact about oncology research is that cancer represents perhaps hundreds of different diseases and will never be a single “magic bullet” drug to conquer all of them. The designed QSAR models must adequately relate the structure of so-called “molecularly-targeted” drug agents to various molecular, cellular and enzymatic mechanisms. The in silico obtained results will be correlated with the corresponding ones, obtained in vitro in cellular and enzymatic systems.

General objective of the project: development, evaluation and validation of a new bioinformatic framework to explore therapeutic activity and therefore increasing the competitiveness of scientific research and innovative national capacity, consolidating partnerships and consortia in health domain. By its general objective, the project gives special synergistic solutions to the complex problem of cancer therapy and offers implementation mechanisms and durability elements.

Specific objectives of the project: research and development of a new biotechnology for modelling information processing mechanisms at biologic level. The project specifically related to delivering for an efficient, originally and specialized software in molecular and QSAR prediction and by this mean, delivering innovative services related to optimized, robust QSAR models for antitumoral and antirheumatic activity in large series of conventional pharmaceutical substances, usefulness in individual therapies.

More effective specific objective and outcome of the project will be improved survival and enhanced quality of life for the vast majority of cancer patients. The project theme is addressing to the FP7 priority domain: HEALTH-2007-1.3-3 Promotion, development, validation, acceptance and implementation of QSARs .

Quantitatively objectives for every year in project development are synthesized in :

An Objectives
2007 Defining the study methodology, the virtual screening of large databases for molecular selection and structural characterization.
2008 Designing, generation of specialized QSAR software. Development of reliable QSAR models for antitumoural activity in conventional drug series. In vitro tests for cellular activity and enzymatic support influences.
2009 Application of the original software to QSAR modelling of cytostatic DMARDs. Assessment of the predicted activity values with in vitro tests, using standardized tumour cell lines.
2010 Development of QSAR models for antitumoral and antirheumatic activity modulation in individualized therapies - QSAR Models Libraries. Assessment of the biological variability in cellular and enzymatic models investigated in vitro. Final documentation for implementation of the created software and assurance durability.

For the achievement of these specific objectives, the activities described in associated work plan and related flow Chart will be carried out. According to our plan, the project structure is for three years and includes activities, logically and rationally grouped into work packages. Briefly, the following types of fundamental research activities will be performed: in silico drug design modelling; application of the original specialized software, and its boosting capacity testing; in vitro tests for assessing the effects exerted in vitro by the therapeutic agents on the cellular metabolism and functionality, on relevant purified enzymatic systems and on the same enzymes in cellular models. Correlation and fitting of the results obtained in silico with those performed in vitro will be performed.