The effect of Alzheimer’s drugs on carbonic anhydrase II and brain pH

Alzheimer’s disease is an important central nervous system disorder, in which beta amyloid, accumulation of hyperphosphorylated tau protein, and oxidative stress are prominent abnormalities. Several factors may influence the process of protein accumulation, such as: increasing temperature, chemical changes, and the effect of pH. Carbonic anhydrase (CAs, EC ۴.۲.۱.۱) which catalyzes the reversible hydration of CO۲ to HCO۳- and protons, plays an important role in pH regulation; Therefore, carbonic anhydrase’s inhibitors and activators are clinically important compounds. The Human Carbonic Anhydrase II isoform, which is expressed in the brain, red blood cells, etc., has the highest catalytic activity. AutoDock, AutoDock vina, Chimera and Chem۳D software were used to investigate the interaction of carbonic anhydrase enzyme II structure (pdb: ۶EQU) with some drug structures extracted from PubChem database. The grid box was set to X=۳۶, Y=۳۴, Z=۴۰ and the number of runs was set to ۱۰ to increase docking accuracy. As carbonic anhydrase is a zinc-containing metalloenzyme; Zinc is attached to Histidine ۹۴, ۹۶ and ۱۱۹ (metal binding site) which is important for the catalytic activity of the enzyme. Also, Histidine=۶۴, the proton shuttle, plays an important role in enzyme activity. The results showed the binding of Donepezil to Histidine=۶۴,۹۴, Galantamine and Tacrine to Histidine=۹۴,۹۶,۱۱۹ and Rivastigmine to Histidine=۶۴,۹۴,۱۱۹, which inhibit carbonic anhydrase enzyme. Memantine was the only drug that did not bind much to the active site of the carbonic anhydrase enzyme. Based on the multiple investigations point to pH reduction resulting in the buildup of amyloid plaques and tau phosphorylation, it appears to be wise when assessing the latest medications utilized to treat Alzheimer’s, to also take into account the drug’s impact on the carbonic anhydrase enzyme and its aptitude in pH control.

کلیدواژه ها:

Alzheimer’s disease ، Brain pH ، Carbonic Anhydrase⇧ ، Inhibitor ، Molecular docking