Laboratory of Drug Design
Summer School of Molecular and Theoretical Biology, 2012
Brief Report
The goal of the project was to give high school students an idea about the modern
rational approaches in the field of drug design. It was supposed that students would
participate in the theoretical stages of drug design – by screening (modeling) the lowmolecular substances regulating the activity of certain therapeutically important target
proteins.
The senior project researchers were Pyotr Vlasov (CRG, Barcelona, Spain) and Polina
Shichkova (MPTI, Moscow). Nine high school students became junior researchers. The
experience of the subsequent work showed that for a purely theoretical project, such a
ratio of senior/junior researchers is adequate.
A kind of an “additional test” was the participation in the project of another pair of
students from Pushchino, which formally did not meet the age requirements of the
School. They fitted quite well in the laboratory teamwork, but in the future it would be
better to form groups of participants on the basis of equal requirements to all, with no
exceptions by the geographical criterion.
Academic process
Quite successful was the experience of joint lectures with another lab, Laboratory of
Protein Modeling headed by Dmitry Ivankov (a theoretical laboratory as well). We
reasoned that understanding of protein physics, the interaction of protein molecules with
each other or with small ligands, as well as modeling of such processes, would require
some common basic knowledge. Thus, our laboratories combined the major theoretical
courses, alternating lectures and lecturers for the joint audience of junior researchers.
We hope that this experiment had a positive effect on the quality of learning. Here are
the major topics covered in the theoretical lectures:
 general principles of protein structural organization. Physics of protein folding;
 diversity of protein structures and functions. Regulation of this diversity at the
genetic level;
 prediction of protein structure and functions;
 inter-protein and protein-ligand interactions. Modeling of these interactions.
We tried to supplement the main material of lectures with some general “hot” topics of
molecular biology and genetics – for example, splicing and RNA interference.
Research process
Our team chose and studied several important target proteins, whose ligands could be
the prototypes of therapeutically active substances. The work of the laboratory included
several blocks:
 analysis of structure and functions of target proteins;
 forming a large list of candidate substances;
 modeling of their interaction with target proteins;
 selection of the most perspective substances as potential ligands.
It is important that the proteins were chosen after consultations with our senior School
colleagues, who are specialists in the corresponding areas (Kondrashov, Ivankov and
Katanaev), and, thus, were related to actual problems of molecular biology. One set of
targets had a relation to the pathogenesis of neurodegenerative diseases, and another
was involved in the regulation of life cycle of tumor cells (Fig. 1). We hoped that
should some perspective theoretical results have been obtained, the most interesting
substances could be tested experimentally.
Fig. 1. Structure of a xWNT-8/Frizzled protein complex. The proteins play an important
role in the development of tumor cells and are “targets” for ligand screening.
The result of work of our “laboratory” was a few advances made by our “junior
researchers”:
 everyone gained some experience of work with a modern professional software
package for modeling of protein-ligand interactions;
 additional experience has been obtained in using various Internet resources of
modern biology – from publication resources to databases of protein structures,
small molecules and drugs;
 using computer modeling, the students selected some low-molecular substances
as potential ligands of several physiologically important target proteins (Fig. 2).
Fig. 2. The results of model fitting of the substance Sorafenib to the sites of the xWNT8 and Frizzled proteins (a few possible positions of the substance is shown).
Continuation of the project
After the School was finished, the project continued to exist. The participants of the
project aim to obtain and publish real scientific results:
 thanks to Vladimir Katanaev, we began experimental testing of the ligands that
showed the best results in the modeling of their interaction with the proteins of
the WNT cascade in tumor cells. Among those substances, one has already
shown its activity. So we decided to continue the tests and to purchase a few
more potential ligands.
 Polina Shichkova made an oral presentation of the project results at the Student
Contest of Research Projects (a part of the 55th Scientific MPTI Conference) and
won the second prize.