Molecular modeling studies upon the hybrid prophylactic agent between 7-methoxytacrine (7-MEOTA) and 4-pyridinealdoxime (4-PA) with different spacer lengths

The novel prophylactic agent 7-methoxytacrine-4-pyridinealdoxime hybrid (called here hybrid 5C) is a hybrid between 7-methoxytacrine (7-MEOTA) and 4-pyridinealdoxime (4-PA) with a 5-carbon length-spacer connecting both molecules. This compound was former designed as a prophylactic agent for intoxication by organophosphates (OP), able to form a complex with acetylcholinesterase (AChE) and reactivate this enzyme in case of OP inhibition. In order to check if the 5 carbons spacer is the ideal to maximize the interactions of this compound inside human AChE (HssAChE), we performed in this work docking, molecular dynamics and mmpbsa studies on a series of analogues of the hybrid between 7-MEOTA and 4-PA, varing the spacer-length from 1 to 10 carbons long. Our results helped to elucidate the interactions of these compounds with the different binding sites inside HssAChE and pointed to the 4 and 5 carbons long as the best spacers for optimizing these interactions.