Molecular modeling and docking calculations of 4-acyloxy-biphenyl-4'-N-butylcarbamates as potential inhibitors of human butyrylcholinesterase

The kinetic studies and drug designs of butyrylcholinesterase play an important role in the development of Alzheimer's disease therapeutics. In this research, automated docking studies were performed to provide useful insights into butyrylcholinesterase inhibition binding modes with designed 4-acyloxy-biphenyl-4'-N-butylcarbamates (compounds 1-8). Moreover, several significant linear correlations between experimental and calculated docking results are observed. Among compounds 1-7, compound 3, which exhibits the strongest hydrophobicity and has four carbonyl hydrogen bindings, shows the highest binding affinity ([K.sub.i] = 1.4 µmol/L) with a binding energy of -7.99 kcal/mol. The observed linear correlation of experimental and calculated inhibition constants ([K.sub.i]) indicates that the molecular docking results are reliable. Moreover, a good linear correlation is observed between calculated binding energies and experimental p[K.sub.i]. The experimental Hansch hydrophobicity constants (π values) are also correlated with the docked binding energy. This study reveals important correlations between butyrylcholinesterase experimental and docking results that contribute to the kinetic based identification of antagonists for the treatment of Alzheimer's disease. Furthermore, these docked models provide important insights into a potential series of 4,4=-biphenolbased inhibitors of butyrylcholinesterase. Key words: brain, butyrylcholinesterase, cholinergic neurotransmission, Alzheimer's disease, molecular docking. On sait que les etudes cinetiques et la modelisation moleculaire portant sur la butyrylcholinesterase jouent un role important dans le developpement d'agents therapeutiques contre la maladie d'Alzheimer. En vue d'acquerir des connaissances utiles sur les modes de liaison permettant l'inhibition de la butyrylcholinesterase, les presents travaux ont porte sur des etudes d'amarrage moleculaire automatise realisees sur des modeles de 4-acyloxy-biphenyl-4'-N- butylcarbamates (composes 1-8). En outre, nous avons observe plusieurs correlations lineaires entre les resultats experimentaux et les calculs de modelisation moleculaire. Parmi les composes 1-7, le compose 3, qui presente la plus forte hydrophobicite et possede quatre groupes carbonyles aptes a former des liaisons hydrogene, montre l'affinite de liaison la plus elevee ([K.sub.i] = 1,4 µmol/L); son energie de liaison etant de -7,99 kcal/mol. La correlation lineaire observee entre les constantes d'inhibition ([K.sub.i]) experimentales et calculees indique que les resultats d'amarrage moleculaire sont fiables. De plus, nous avons observe une correlation lineaire satisfaisante entre les energies de liaison calculees et les valeurs experimentales de p[K.sub.i]. Les valeurs experimentales des constantes d'hydrophobicite de Hansch (valeurs π) sont egalement correlees avec l'energie de liaison obtenue par modelisation. En somme, cette etude revele d'importantes correlations entre les resultats experimentaux et les calculs d'amarrage moleculaire a la butyrylcholinesterase, lesquelles contribuent a l'identification fondee sur la cinetique d'inhibiteurs pour le traitement de la maladie d'Alzheimer. De plus, ces modeles d'amarrage moleculaire permettent d'obtenir d'importantes connaissances sur une serie d'inhibiteurs de structure 4,4'-biphenolique contre la butyrylcholinesterase. [Traduit par la Redaction] Mots-cles : cerveau, butyrylcholinesterase, neurotransmission cholinergique, maladie d'Alzheimer, amarrage moleculaire.
Introduction Alzheimer's disease (AD) is an irreversible but progressive neurodegenerative disorder that is caused by the loss of synapses and neurons in the certain subcortical regions and cerebral cortex. Previous [...]