The Role of Protein Conformational Switches in Pharmacology: Its Implications in Metabolic Reprogramming and Protein Evolution

Besides pharmacogenomics and drug dynamics, pharmacological properties of a drug could also arise from protein conformational switches. These switches would arise from the following mechanisms: (a) slight shifts away from a protein’s native conformation induced by mutation, (b) changes in the protein’s environment allowing for structural rearrangements to form hitherto unknown conformations, (c) parsing the protein into foldable polypeptide fragment(s) by either proteolysis of the native structure or (d) perturbation of the native conformation to generate polypeptide fragment(s). These switches are modulated by changes in the protein’s matrix properties such as pH, temperature, ligands—their nature, concentration and complexes; micronutrients, oxidant/antioxidant status and metabolic products within the functional environment of the protein. The pharmacological implications of these are discussed in light of polypharmacology arising from protein isomerism, cross-pharmacology, possible decreases in both the expressible and expressed protein population and metabolic reprogramming—and ultimately, how these factors relate to diseases. Further implications include variational drug toxicity and drug response idiosyncrasies. Another important consequence is that the “whole life” history of the individual would play an active role in that individual’s response to disease severity and drug response up to that very moment and is prone to variations with changes in pre-disposing factors.