Estudos cristalográfico e quantum-mecânico da reatividade de um composto derivado diidroisoxazol (CL3ONA) frente à enzima Acetilcolinesterase (AChE)

Abstract

The compounds with anticholinesterase action are the target of the pharmaceutical industry, because they are tied in information transmission mediation in the nervous and muscular system from the inhibition of acetylcholinesterase. Thus, the anticholinesterase compounds constitute a means of combating neurodegenerative diseases. However, the continued use of such compounds has side effects and its action is different for each patient. It is therefore important to develop new compounds with anticholinesterase action. Given this panorama, this paper analyzes the interaction of the molecule (E) -1,1,1-trichloro-5,5-difenill-4-metoxipent-3-en-2-one (CL3ONA) with acetylcholinesterase (AChE) in theoretical level. To this end, the structure of the molecule was determined by X-ray diffraction and analysis of substrate-enzyme interaction performed through molecular modeling level electronic structure. After the study has been observed that CL3ONA has two regions susceptible to nucleophilic attack by the serine ACh: i) the carbonyl carbon, and ii) the carbon-β unsaturated carbonyl; which in turn provides two mechanisms for the action of the molecule in the inhibition of AChE, respectively: i) classical nucleophilic addition to carbonyl and ii) Michael Addition. In the competitive inhibitory action was studied the mechanism of inhibition in the CL3ONA not interact with the catalytic triad (non-competitive). Analysis of Natural connection orbitals made the competitive mechanism according to classical nucleophilic addition to the carbonyl interaction of CL3ONA front AChE, as this shows: i) increased number of interactions with amino acid residues; ii) significant amounts of delocalized electron energy for such interactions.