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The drug discovery process is inherently long and costly, prompting the development and integration of computational tools to mitigate these challenges. One of area explored in computer-aided drug discovery is to understand the role of solvation in protein-drug binding and to develop computational tools and methods that can be integrated in the drug discovery process. Grid Inhomogeneous Solvation Theory (GIST) is a tool that provides a framework for mapping solvation thermodynamic properties of water molecules on the protein surface. This thesis explores the use of GIST in generating pharmacophore models and elucidates the role of solvation in protein structural fluctuations.
One of the fundamental tenets of molecular recognition is that a drug must have charge and shape complementarity with the protein. Meaning that the drug must fit inside the protein’s binding pocket and make necessary interactions with the protein’s surface. In the absence of a bound ligand, water molecules often mimic ligand interactions with the protein surface by donating and accepting hydrogen bonds or forming hydrophobic contacts. Additionally, water adapts to protein structural fluctuations and shifts in the binding cavity’s shape. We present a method to identify high water density regions (hydration sites) on protein surfaces GIST. Through this approach, we identify the interactions at these hydration sites, evaluate their thermodynamic and solvation properties, and develop water-based pharmacophores to aid in pose prediction and virtual screening.
Our findings reveal that water does not always make full complementary interactions when the protein’s motion is restrained. This led us to investigate how solvation thermodynamics vary with protein structural fluctuations. We analyzed the solvation thermodynamics within the binding cavities of an explicit molecular dynamics simulation, comparing scenarios in which protein side chains are flexible versus restrained. We found that the solvation thermodynamics is more favorable when the protein’s side chains are allowed to move. This indicates that the reorganization of the protein impacts the structure and the solvation of the binding pocket and there is a solvation cost on sampling protein structures that are complementary to a chemical matter.
In summary, these thesis aims to understand the role of solvation thermodynamics on the protein surface and how it can be incorporated in the drug discovery process.
