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MOLECULAR MODELING OF BUTYRYLCHOLINESTERASE INHIBITORS AS POTENTIAL DRUGS AGAINST ALZHEIMER’S DISEASE

MOLECULAR MODELING OF BUTYRYLCHOLINESTERASE INHIBITORS AS POTENTIAL DRUGS AGAINST ALZHEIMER’S DISEASE

Bárbara B. Novo, Joelma F. de Mesquita, Camilo H. S. Lima and Magaly G. Albuquerque

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide. According to the World Health Organization (WHO), it is estimated 152 million people worldwide will be affected by AD in 2050. Memory loss, a symptom of AD, is the result of a decrease of acetylcholine level in the brain, due to the increase in cholinesterases, mainly butyrylcholinesterase (BChE). Our study targets new potential BChE inhibitors, by molecular modeling, aiming to alleviate the symptoms from the acetylcholine deficit. We used two 3D structures of human BChE complexes with potent inhibitors, resolved by X-ray diffraction and available in the Protein Data Bank (PDB): 5DYW and 5NN0 (Košak et al., 2016, 2018). The inhibitors have a piperidine heterocycle showing (R) configuration at C3 of the piperidine ring, whose amino group is protonated, according to Košak et al. (2016, 2018). The construction of the 3D structures of the inhibitors (5HF601 in the 5DYW complex and 92H627 in the 5NN0 complex) was carried out in the Spartan’14, followed by geometry optimization and conformational analysis (systematic and random), using the MMFF94 force field. Molecular docking/redocking was performed on the DockThor server (https://dockthor.lncc.br/v2/), where the C-alpha from Gly116 (chain A) at the active site, was chosen as the center of the 20x20x20 Å box. The preliminary results indicate that, for both ligands, the poses with the best score refer to the structures where the absolute configurations of both, C3 and N of piperidine, are (S). In the case of C3, according to Košak et al., the configuration is (R), while the configuration of the protonated N is not described, probably due to the possibility of both configurations coexisting in equilibrium. Thus, our study suggests re-evaluating the configuration of these stereogenic centers. As a perspective, we will study the binding modes of other inhibitors.