Science

SCIENTIFIC BACKGROUND OF THE PROJECT

1) Goal of research - stem cell biology in cancer and degenerative diseases.

First of all the main difference is the research area. Our project is  devoted to studies of molecular structure and in silico drug design for proteins, which participate in stem cells biology. The main goal for our drug discovery research is to find drug-like compounds which can be used in stem cells based regenerative medicine and regenerative medicine, based on somatic cells transplantation. So first, the main difference is the goal of the project to find drug candidates which can be used for treatment of degenerative diseases, like Alzheimer's disease and osteoporosis. As far as stem cells biology is linked to cancer research the second area of our interest is cancer. 

2) Main objects of the research

The fundamental research on protein folding and structure are not the main purposes of the project. The knowledge about protein structure and mechanisms of function for us is only the first step toward in silico drug design of small molecule compounds, which act on these biological targets. Of course we hope that we’ll refine some interesting protein spatial structures and maybe will make some insights in some mechanisms of protein functions, but this is just the first step.

The second step is drug discovery based on flexible virtual screening for different types of chemical compounds databases of organic compounds. For the most prospective among them we plan to assess their binding mode with biotargets by use of high-throughput molecular dynamics.

3) Software

We plan to bring together to the project all software aimed to in silico drug discovery, including protein structure modeling methods, hit identification and post-processing of the results by QSAR methods. Some will be used as distributed computing applications (as GROMACS and Autodock) and some will be used as offline applications. We also would like to evaluate the predictive power for computed based methods in drug discovery. So we plan to get focused diversity data-sets of organics compounds aimed to biological trials as the main product from the project.

4) Collaboration to wet lab experiments.

The main purpose of this project is not only to make scientific papers on fundamental aspects of protein functions and make some computer research but the further development of in silico results by transfer to biological trials and lead optimization for the identified hits.

MORE ABOUT RESEARCH AREA AND PROJECT BACKGROUND

First of all we are looking for compounds which can be used for regulation of adult stem cells activities in so called “stem niches”. Stem niches – are the compartments in which adult stem cells are placed all over the human body. These niches are widespread in most of the tissues (it can be hypothesized that in all of the tissues) in old peoples as in young ones (but in old in less extent). These are partially stem cells, which participated in embryonal development and then stopped the generation of new tissues and went to the dormant (sleep) state and are awakened time to time in some tissues by stem niche signals.

The uncontrolled division of such stem cells leads to cancer transformation and immortalization. From the other side the mechanisms in human body which control stem cells in stem niches prevent the direct usage of stem cells in regenerative therapy (and they must! – to prevent cancer and uncontrolled division). So our hypothesis is that the fine-tuned regulation of balance between regenerative activity of stem cells and cancer can be achieved by targeted regulation of growth factors and signaling proteins, regulating activities of stem cells in stem niches.

According to our hypothesis such fine tuned regulation can be used for treatment of various types of cancer and for induction of regeneration of different types of tissues even in old organisms. The first protein candidates for such regulation are the next signaling pathways: Wnt/Frizzled, Shh/Smoothened and Notch. The next goals are of course dozens of related growth factors. The work scheme can be seen are pic.1 below.


PATHWAY MAPPING AND SYSTEM BIOLOGY

For fine tuning of stem cells activities in stem niches mentioned above is a complicated task, related to correct mapping of pathways. So one of the our tasks is to make online server with interactive signaling pathways maps, resulted from system biology data analysis. This is not related to distributed computing, but also is planned to be part of our project.

Also as not distributed computing parts we plan to make development of several applications for computer assisted drug design.

 
 

Pic. 1. This is a simplified general scheme of the project background. The first part for our project is molecular modeling of spatial structure for main participants in Wnt/Frizzled, Shh/Smoothened and Notch pathways and in silico design of their agonists and antagonists. The second part is devoted to biological trials and in silico lead optimization. The other part of the project is pathway mapping devoted to understanding of stem niches regulation maps in different types of tissues and understanding of intersection between stem cells signaling pathways maps and cancer cells signaling pathways maps (see Mapping) .

SOFTWARE APPLICATIONS DEVELOPMENT

Some areas of algorithms development that are extremely interesting for us and which we try to develop for distributed computing:

1) Development of force fields for small molecules  by quantum chemistry methods as one of the possibilities.

2) Implementation of number of software for distributed computing environment: ligand-based screen software, 3D conformations generation, QSAR and chemical databases profiling methods.

3) Evaluation of different conformational sampling methods, which can save some computational time and increase  probability for identification of global energy minimums for protein and protein-small molecule 3D structures.

4)  Developing for GPU versions for software applications mentioned above.