engleski

In silico design of high affinity acetylcholinsterase inhibitors

Role of acetylcholinesterase (AChE) in pathology of neurodegenerative diseases as myasthenia gravis, Parnkinson or Alzheimer disease initiates development of reversible AChE inhibitors. Active site of AChE, 20 Å deep and 5 Å wide, defines interaction site for substrate and inhibitors. Catalytic triade is located at the bottom of an active site (Ser203, His447, Glu334) with an oxyanion hole (Gly121, Gly122, Ala 204), a choline binding site by Trp86, Tyr337 and Phe338, and a peripheral binding site by Tyr72, Tyr124 and Trp286. Crystallographic analysis of various AChE inhibitor complexes show that most of inhibitors form interaction with peripheral and/or choline binding site of AChE. We studied possibility of third binding site for high affinity inhibitors designed in silico. These new inhibitors form interaction with peripheral and choline binding site and additional interactions with residues Ser203, Gly121 and Gly122. These glycines are members of the oxyanion hole. Affinity of novel inhibitors were estimated using following scoring functions: PLP2, PMF, PMF04, Jain and LigScore1_Dreiding. By comparing scoring of known high affinity AChE inhibitors and those tested here we conclude that AChE may have higher affinity for new inhibitors due to additional stabilisation with residues from oxyanion hole via hydrogen bonds.

reversible inhibitors; third binding site; high affinity inhibitors

nije evidentirano