QSAR and molecular docking study for uncharged acetylcholinesterase reactivators inhibited by organophosphate

Abstract

Organophosphate can be toxic to humans by inhibiting the acetylcholinesterase which plays an important role in the nerve impulse transmission system. Poisoning of this compound can be treated by uncharged compounds as acetylcholinesterase reactivators which work in the central nervous system. The purpose of this study is to create a QSAR modeling, designing new reactivators and perform molecular docking to find reactivators with better activity. Two QSAR equation models were obtained as follows: Model 1: logIC50 = 0.1943 (±0.0475) [RDF115u] - 0.0910 (±0.0668) [RDF155e] - 0.1115 (±0.0142) [RDF25i] - 17.7959 (±4.8605) [E1e] + 16.0383 (±2.6845). Model 2: logIC50 = 0.1992 (± 0.0464) [RDF115u] – 0.2658 (± 0.1751) [RDF155p] - 0.1126 (± 0.0136) [RDF25i] - 18.1643 (± 4.7041) [E1e] + 16.2485 (± 2.5996). Three design compounds with the best activity prediction of QSAR modeling were used for molecular docking. logIC50 prediction values of reactivators U1, U2 and U3 from model 1 were respectively 1.19, 0.103 and 0.142. The result of logIC50 prediction from model 2 is 1.33, 0.203 and 0.179 respectively. Molecular docking showed that the design compound interacted with the same enzyme residues as the native ligand with docking scores of U1, U2, U3 reactivator respectively -9.5, -9.7 and -9.1 kcal/mol. These results indicate that the design compounds have better activity than previous studies and the potential to be used as an organophosphate-inhibited acetylcholines-terase reactivator.