%0 Journal Article
%T Molecular Modeling Studies of Piperidine Derivatives as New Acetylcholinesterase Inhibitors against Neurodegenerative Diseases
%A Elaine F. F. da Cunha
%A Jos¨¦ E. Resende
%A Tanos C. C. Franca
%A Mateus Aquino Gon£¿alves
%A Felipe R. de Souza
%A Let¨ªcia Santos-Garcia
%A Teodorico C. Ramalho
%J Journal of Chemistry
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/278742
%X Neurodegenerative disorders are related to the progressive loss of structure or function and, eventually, death of neurons. These processes are responsible for diseases like Parkinson¡¯s, Alzheimer¡¯s, and Huntington¡¯s, and the main molecular target for the drug design against these illnesses today is the enzyme acetylcholinesterase (AChE). Following this line, in the present work, we applied docking techniques to study some piperidine derivative inhibitors of AChE and further propose structures of six new AChE inhibitors as potential new drugs against neurodegenerative disorders. The best inhibitor proposed was submitted to additional molecular dynamics simulations steps. 1. Introduction Skeletal muscle ontogenesis is a complex and multistep process during which myoblasts, the skeletal muscle progenitors, proliferate, migrate, and fuse into myotubes [1]. The latter are then innervated, and the nerve endings govern the final phases of maturation of myotubes into the functional skeletal muscle fibres responsive to nerve inputs [2]. Regular transmission of these inputs is directly related to the action of acetylcholinesterase (AChE), an enzyme present in the neuromuscular junctions and responsible for the hydrolysis of the neurotransmitter acetylcholine. In some neurodegenerative disorders, like myastimiahenia gravis or Parkinson¡¯s disease, inhibition of AChE is a fundamental therapeutic step [1, 3]. Several clinical studies on AChE inhibitors, such as physostigmine and tacrine, have revealed interesting results. However, side effects and oral activity restrict the application of these agents as effective drugs. In this context, recent findings show that piperidine derivatives are promising AChE inhibitors able to overcome the unfavorable side effect profile and poor pharmacokinetics related to the aforementioned compounds. Despite great importance, the study of the interaction between piperidine derivatives and AChE has received remarkably little attention. The interactions of AChE with its inhibitors, however, are not fully understood yet and still deserve investigation. The drug design of rational therapy requires insight into the molecular mechanisms underlying the AChE-inhibitor interactions under physiological conditions in order to propose structures of new and more efficient inhibitors. In this line, molecular mechanics based methods involving docking studies and also molecular dynamics simulations are suitable tools to adjust ligands at target sites and to estimate interaction energy (affinity) [4]. Nowadays, that is a well-established technique
%U http://www.hindawi.com/journals/jchem/2013/278742/