Molecular modelling studies on the interactions of 7-methoxytacrine-4-pyridinealdoxime with VX-inhibited human acetylcholinesterase. A near attack approach to assess different spacer-lengths

Publication date: Available online 21 May 2019Source: Chemico-Biological InteractionsAuthor(s): Jorge Alberto Valle da Silva, Eugenie Nepovimova, Teodorico Castro Ramalho, Kamil Kuca, Tanos Celmar Costa FrançaAbstractThe novel prophylactic agent 7-methoxytacrine-4-pyridinealdoxime is a hybrid compound that was formerly designed to keep acetylcholinesterase resistant to organophosphates inhibitors and to reactivate that enzyme in the case of intoxication by such inhibitors. In rational design, a 5-carbon length-spacer hybrid compound was synthesized to evaluate its inhibitory and reactivation capabilities. In this work, theoretical results were achieved through molecular modelling techniques, taking for granted enzymatic reactivation reaction by nucleophilic substitution. Based on the near attack conformation approach, docking studies were performed to assess the spacer-length from 1 to 10 carbons long of a series of analogues of the 7-methoxytacrine-4-pyridinealdoxime hybrid compounds. Consequently, the hybrids compounds with length-spacer of 4 and 5 carbons long were the best assessed and subsequently subjected to further molecular dynamics simulations, complemented by Poisson-Boltzmann surface area calculations. As a result, intermolecular interactions with the different binding sites inside human acetylcholinesterase were elucidated. Besides, thermodynamics and kinetics concepts pointed to the 4-carbon linker as optimum for enzymatic reactivation. Further studies, based o...
Source: Chemico Biological Interactions - Category: Biochemistry Source Type: research