First principles calculations of thermodynamics and kinetic parameters and molecular dynamics simulations of acetylcholinesterase reactivators: can mouse data provide new insights into humans?

Abstract

We have applied a theoretical methodology, previously developed to evaluate the association and kinetic reactivation constants of oximes, comparing theoretical data obtained for human acetylcholinesterase (HsAChE) with in vitro results from Mus musculus AChE (MmAChE) previously reported in the literature. Our results, further checked by additional molecular dynamics simulations steps, showed a good correlation between the theoretical and experimental data, supporting the methodology as appropriate for prediction of thermodynamic and kinetic parameters and corroborated MmAChE as a suitable model for studies with HsAChE.

Keywords:

• acetylcholinesterase
• QM/MM
• chemical mechanism of reactivation
• neurotoxic agents

Acknowledgments

The authors are grateful to Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG) (TCR and EFFC), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (KSM), Fundação de Amparo ao Ensino e Pesquisa do Estado do Rio de Janeiro (FAPERJ) (TCCF) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (TCR and EFFC) for financial support. We also would like to thank the Centro Nacional de Processamento de Alto Desempenho em São Paulo (CENAPAD-SP) for the computational facilities. This study was also supported by Project No. FVZ0000604 (KK).