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Advancements in computational techniques have revolutionized structure-based drug design, substantially improving the efficiency and effectiveness of the drug discovery process by reducing time, costs, and labor requirements. These advancements include various methods, such as investigating small molecule ligands binding to proteins, exploring alternative protein conformations, and solvation mapping on the protein surfaces. Among these methods, understanding the correlation between protein–ligand binding and the role of solvation is important.
A fundamental concept in protein–ligand binding is shape and electrostatic complementarity, which is complicated by the inherent flexibility of proteins. In the absence of small molecule ligands, proteins are complementary to surface water. Water plays a crucial role in stabilizing protein structures by altering its interactions with the protein surface and differently occupying cavities based on their various shapes. This thesis focuses on the role of protein surface water, emphasizing the importance of flexible protein conformations and utilizing water to aid in the drug discovery process.
In the study of solvent thermodynamic barriers to the formation of cognate binding sites, we examine how solvent thermodynamics fluctuate as proteins adopt different conformations. We map out solvation thermodynamics on the protein surface using Grid Inhomogeneous Solvation Theory (GIST) and analyze the thermodynamic changes within the binding cavities of conformations where side chains are mobile, comparing these to conformations where they remain fixed, as in the cognate bound structure. We identify motifs that present significant barriers to the sampling of cognate structures and differences in the complementarity of surface water to rigid and flexible conformations. Here, we demonstrate that understanding the interplay between solvent thermodynamics and protein structural fluctuations is crucial for discovering alternative binding pockets and assessing the displacement of water sites upon ligand binding, potentially enhancing the efficacy of lead molecules.
We then discuss the potential use of water as a pharmacophore model. The water-based pharmacophore model arises from the idea that water has charge and shape complementarity to the protein surface. Water mimics and replicates the interaction between the protein and the ligand, and effectively occupies the binding site as the cognate ligand does. We identify the charge complementarity of water by comparing it with protein–ligand cognate interactions and generate the shape features of water using the structural environment of the water network within the binding cavity. We employ this approach to generate a water-based pharmacophore model and use it in pose prediction as a validation approach.
Our project on the solvation thermodynamic and structural maps of SARS-CoV-2 targets is published to offer an online public repository, aiding both academic and industrial pursuits in identifying small molecule treatments for COVID-19. The online repository encompasses solvation maps using Grid inhomogeneous Solvation Theory (GIST), 3D Reference Interaction Site Model (3D-RISM), and Solvent Structure and Thermodynamic Mapping Hydration Site Analysis (SSTMap HSA). Additionally, applications of these solvation maps in drug design efforts are introduced.
In summary, this thesis aims to suggest various approaches to incorporating protein surface water into computer-aided drug design. We map out solvation thermodynamics on the protein surface and present methods for utilizing these maps. We identify the impact of solvent thermodynamics on sampling protein conformations and posit that the solvent may impose energetic barriers to forming the cognate conformation. We also present a pharmacophore model derived from solvation thermodynamic mapping by using the electrostatic and shape features of water within the protein binding site. Finally, we introduce an online repository of solvation thermodynamic and structural maps of SARS-CoV-2. We hope our comprehensive research on solvation thermodynamics on protein surfaces contributes to groundbreaking solutions that enhance therapeutic outcomes.
