Histamine Bis-spinaceamine Derivative As Activator Of Human Carbonic Anhydrase Enzyme For Artificial Tissues Engineering: A DFT Study

Enzymes are proteins that have a specific function. They speed up the rate of chemical reactions in a cell or outside a cell. Enzymes act as catalysts; they do not get consumed in the chemical reactions that they accelerate. Indeed, carbonic anhydrases (CA, EC 4.2.1.1) are metallo-enzymes, usually using Zn(II) ions within their active site for performing the efficient hydration of CO2 to bicarbonate and protons [1, 2].Some of histamine bis-spinaceamine derivatives, Figure 1, were investigated as activators of human (h) carbonic anhydrase isoform IIV, the cytosolic hCA VII. This isoform of CA enzyme was effectively activated by this new histamine derivative [3]. As all CA activators (CAAs), these new classes of enzyme modulators also participate in the catalytic cycle of the enzyme. The activator molecule participates to the rate-determining step of the catalytic cycle, that is, the proton shuttling between the zinc-coordinated water molecule and the environment, with the formation of the zinc hydroxide species of the enzyme [4]. As CA activators recently emerged as interesting agents for enhancing cognition, in the management of CA deficiencies, or for therapy memory and artificial tissues engineering, our studied compounds may be considered as candidates for such applications. According to the advances in computational processing power in these years, more techniques that are refined have become available, and density functional theory (DFT) has been established as one of the main methods for calculation on different compounds. With this goal, we study the complexation of these new activators to the active center of CA enzyme from different directions thermodynamically and compare our results with experimental data to confirm the accuracy of level of calculations.

Keywords:

Carbonic anhydrase enzyme , histamine derivatives , Activators , DFT calculation , Artificial tissues engineering