Molecular Pharmacology Laboratory

• The Laboratory has built a full-scale model of the p53 tumor suppressor protein. We have developed selective reactivators of the p53 protein. These substances inhibit the E3 ligase ferment that causes premature degradation of the p53 protein that is able to cause death of cancer cells. New molecules have been created on the basis of a deep study of the structure of the MDM2 target proteins and modeling of the process of its interaction with the p53 tumor suppressor protein. Works published in 2013–2018 reflect successful development of a new pharmacophore hybothesis based on creation of ab additional binding center of the smaller molecule with the active cavity of the MDM2 oncogene. The initial hypothesis has been formulated on the ground of computer modeling and proven by a complex of tests on protein and cell models. Compounds created in accordance with the new strategy have shown activity that is by an order of magnitude higher than than that of initial analogs.
• We have developed selective low molecular activators of AMPK – the protein that is the key regulator of the energy balance both at the cell level and at the level of the whole organism. Regulating activity by AMPK allows to compensate negative consequences of the metabolic syndrome – a complex of functional malfunctions that is one of the most widespread diseases of out time.
• Such work is possible thanks to combination of the three main components of medical chemistry in one laboratory – highly productive computations, chemical synthesis and research of targeted biological activity of created low-molecular compounds.

Implemented results of research:

• A number of methods developed by the Laboratory and related to creation of new pharmaceutical agents (methods of computer modeling, creation of cell models and research of targeted activity) have found applications in in conducting works of similar profile in such organizations as the Research Institute of Hygiene, Occupational Pathology and Human Ecology of the Federal Medical-Biological Agency of Russia (Russia), the Research Institute of Highly Pure Biopreparation of the Federal Medical-Biological Agency of Russia (Russia), the Institute of Cytology of the Russian Academy of Sciences (Russia), the Saint Petersburg State University (Russia).
• Two agents created by the Laboratory are currently undergoing testing on model animals. One agent has been tested on volunteers in collaboration with Research Institute of Hygiene, Occupational Pathology and Human Ecology of the Federal Medical-Biological Agency.

Education and career development:

• We have developed five educational courses for the specialization «Molecular and cell biotechnology»: «Inhibition of protein-protein interactions in in creation of pharmaceutical agents», «Methods of research of kinase activity based on FRET», «Modern tendencies of molecular docking», «Low molecular regulators of the cell cycle», «Methods of highly efficient screening».
• Two international conferences and two international schools have been organized internships and short-term training at largest international research centers.

Organizational and structural changes:

• On the grounds of the Laboratory we have organized the Research and Education Center «Molecular pharmacology».
• A collective usage center is currently being formed. It will allow to conduct phenotype screening of low molecular compounds and primary determination of molecular targets mediating the researched effect (the «Operetta» imaging system combined with robotized supply and a high density DNA microchip scanner).

Collaborations:

• MRC Toxicology Unit (United Kingdom), University of Rome Tor Vergata (Italy): joint research, training postgraduates, student exchange
• Research Institute of Hygiene, Occupational Pathology and Human Ecology of the Federal Medical-Biological Agency of Russia (Russia): joint research, conducting scientific events
• Institute of Cytology of the Russian Academy of Sciences (Russia): joint research, conducting scientific events, training postgraduates, student exchanges
• Saint Petersburg State University (Russia): joint research