Concept and objectives. The concept of the Checosp project focuses on the development of novel integrated methods of computational and synthetic chemistry that advance the mechanistic understanding of the role of dynamics in protein interactions at the atomic level and then translate this information into new molecular design rules for the discovery of modulators of fundamental signaling pathways. The overarching goal is to design and synthesize new molecular entities able to act as chemical switches that turn on/off specific cell functions by tweaking the internal dynamics of the specific nodal proteins they target. In this framework, the new fundamental challenge for chemistry consists in identifying privileged structures capable of selectively interfering with key functional sub-states of central regulators of the networks underlying signaling pathways, thus allowing to tune, and not only inhibit, entire signaling cascades that control cell life. In chemical and molecular design terms this represents a shift of paradigm that poses a number of new challenges and perspectives.
To meet these challenges, we will develop and optimize new computational chemistry methods based on the promise of our recent theoretical progresses in the identification of functional sub-states from the analysis of protein internal dynamics and energetics, and will merge them with experimental drug design methods based on advanced synthetic approaches. In turn, this will allow to enhance our understanding of complex biomolecular systems and increase the efficiency with which appropriate chemical modulators of signaling pathways can be identified. Importantly, this might lead to the development of global pathway inhibitors and regulators with unique therapeutic potential.
Here, we will focus on the networks of the 90 kDa heat shock protein (Hsp90). Hsp90 is a nodal protein at the crossroad of multiple cell functions, which orchestrates different integrated cellular pathways required for cell development and maintenance. Hsp90 has been shown to play a key role in cancer, for which inhibitors are urgently needed, and in the growth/differentiation processes of stem cells, for which chemical modulators (effectors) that help direct cells towards different states may represent an important medical breakthrough. Hsp90 activities are strictly dependent on its conformational dynamics and on the ligand-mediated transitions among different conformational sub-states endowed with different functional properties. For all these reasons, Hsp90 constitutes an ideal target for our project.
In this project, we have brought together two recognized groups with complementary expertise with the common goal of bridging computational and synthetic chemistry. Validation of the new molecular design concepts and analysis of the resulting molecules will be carried out with experimental tests ranging from binding studies, to the characterization of the modulator effects of the discovered molecules in human cell models including mesenchymal stem cells and different tumor cell lines.
For its unconventional nature, based on understanding the link between protein dynamics and interactions in directing drug design, this approach has no precedent in the field of medicinal chemistry. While based and motivated by the study of molecular chaperones, the idea behind the strategy we propose is general and immediately transferable to other protein targets and networks.