Targeting Fundamental Aspects of Protein-Ligand Interactions to Improve Computer-Aided Molecular Design
Abstract
Molecular recognition, based on highly complex non-covalent interactions between protein and ligands, plays key roles in biological processes. Thus, knowledge of the process is crucial for understanding phenomena at all biological levels and for many applications, notably drug discovery. However, we lack sufficient fundamental knowledge and robust experimental data to elucidate and rigorously model the interactions involved. This is a major obstacle to the efficient solution of diverse medical and biological problems.
Therefore, in the proposed research we will design and synthesize novel sets of small organic molecules to be used as chemical probes to target fundamental questions of protein-ligand interactions, including the electronic properties of non-covalent interactions, enthalpy and entropy components, dynamics, on-off rates and solvent effects. In intense inter- and multi-disciplinary efforts, we will combine organic synthesis with state-of-the-art and novel techniques (experimental and computational) to explore three medically important protein-ligand systems. We have formulated sets of four sub-projects and goals, which will individually will yield new methods and knowledge in bioorganic, medicinal and computational chemistry. They will all also contribute to a unique long-term objective: to link interactions at atomic levels (geometries and energies) to molecular level interactions (dynamics, thermodynamic and kinetic profiles) and ultimately to cellular responses, providing the foundations for a new paradigm that we call translational chemistry.
Even if only partially successful, this research will provide: novel insights into protein-ligand interactions and their effects on biological processes; major revisions of established perceptions in medicinal chemistry; and radically new predictive methods for use in molecular design and various other applications, thereby accelerating the discovery of drugs and agents for other purposes.
The computational chemistry will include geometry optimisations and energies of protein and ligands using quantum mechanics, and molecular dynamics simulations of protein and ligands.
