Exploring protein – ligand interactions: from mechanistic insight to inhibitor development
Loading...
Date
2024-08-26
Authors
Legare, Scott
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Biological processes required for life can be understood by studying the underlying molecular
and chemical processes which give rise to these biological processes. Proteins are the primary
functional molecules of biological systems where they serve as catalysts, cell signaling
molecules, receptors and also serve structural and mechanical roles. In order to perform these
various functions, proteins must physically interact with other molecules referred to as ligands.
Therefore, developing a detailed understanding of protein – ligand interactions from a chemical
and molecular perspective improves the understanding of the biological processes which these
interactions give rise to. A detailed understanding of these protein ligand interactions also
enables the development of drugs capable of disrupting or modulating protein – ligand
interactions for the treatment of diseases. In other cases, the study of protein – ligand
interactions can be used to develop new and useful biotechnologies. Many techniques can be
useful for studying protein – ligand interactions including structural, computational, and
biophysical techniques. Of these, biophysical techniques often provide the greatest deal of
foundational insight into the nature of the protein – ligand interactions. In addition, a biophysical
characterization of a protein – ligand interaction is often a prerequisite for the development of
drugs and biotechnological applications for these protein- ligand interactions.
Three unique protein – ligand interaction systems are explored in this thesis, using a
combination of structural, computational, and biophysical techniques. In the first part of this
thesis the interaction between the Laminin N-terminal domain and Ca2+ is explored using a
combination of structural, computational, and biophysical techniques. From this approach, a
detailed understanding of the molecular basis and functional properties of the interaction
between the Laminin N-terminal domain and Ca2+ is developed. In the next part of this thesis,
the biophysical and enzymatic characterization of the SARS-CoV-2 Main protease is performed.
Guided by this biophysical and enzymatic characterization, an improved substrate for
high throughput screening is developed. The final part of this thesis performs a thorough
examination of the interaction between Netrin-1 and UNC5B including the requirement for a
heparin co-receptor. From this examination of the Nertrin-1 UNC5B interaction, peptide
inhibitors of the interaction are rationally designed. Together the work presented in this thesis
demonstrates the study of multiple aspects of protein - ligand interactions. It combines studies
aimed at gaining an understanding of molecular basis and functional properties of protein –
ligand interactions, developing methods to identify and test inhibitors of protein – ligand
interactions, and leveraging the gained understanding to rationally design inhibitors of protein-
ligand interactions.
Description
Keywords
Protein - ligand interactions, ligand interactions, Protein