Quantum Methods in Drug Discovery: An Introduction to the Theoceptor (Theoretical Receptor) Approach

In this chapter, we introduce the theoceptor method. The method seeks to achieve a fully quantum mechanical computational description of protein-ligand binding. To do this, semi-empirical quantum mechanics levels of theory are applied during geometry optimization, with higher levels of theory applied as single point energy evaluations. The system is represented by subsets of the atoms of the protein receptor selected according to proximity to the ligand; backbone and C_β atoms are kept fixed during optimization with other atoms being free to move. The method has been applied to enzymes, GPCRs, ion channels, and inhibitors of corrosion at metal surfaces. Examples described reveal that the method complements structural biology well by enhancing and correcting interpretations, can be applied to X-ray crystallography- or cryo-electron microscopy-derived structures, can be applied equally to covalent and noncovalent binders, can provide excellent predictions for the changes in activity between matched molecular pairs, and can assign mode of action, such as agonist or antagonist.