Scale Alpha and Beta of Quantitative Convergence and Chemical Reactivity Analysis in Dual Cholinesterase/Monoamine Oxidase Inhibitors for the Alzheimer Disease Treatment Using Density Functional Theory (DFT)
Molecular quantum similarity descriptors and Density Functional Theory (DFT) based reactivity descriptors were studied for a series of cholinesterase/monoamine oxidase inhibitors used for the Alzheimer's disease treatment (AD). This theoretical study is expected to shed some light onto some molecular aspects that could contribute to the knowledge of the molecular mechanics behind interactions of these molecules with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamine oxidase (MAO) A and B. The Topogeometrical Superposition Algorithm to handle flexible molecules (TGSA-Flex) alignment method was used to solve the problem of the relative orientation in the quantum similarity (QS) field. Using the molecular quantum similarity (MQS) field and reactivity descriptors supported in the DFT was possible the quantification of the steric and electrostatic effects through of the Coulomb and Overlap quantitative convergence scales (alpha and beta). In addition, an analysis of reactivity indexes is development, using global and local descriptors, identifying the binding sites and selectivity in the (cholinesterase/monoamine oxidase) inhibitors, understanding the retrodonor process, and showing new insight for drugs design in a disease of difficult control as Alzheimer. 1. Introduction Alzheimer’s disease (AD) is considered a chronic disease with serious implication and many consequences. AD not only has enormous implications from the medical point of view but also has high economic costs and a negative impact on social activities within families and work places of the AD affected patients. AD is clinically characterized by progressive loss of memory and a decline in language skills and other cognitive impairments that inexorably leads to incapacitation and finally to death [1–7]. AD is characterized by the development of amyloid plaques and congophilic angiopathy in the brain cortex and hippocampus; it has been accepted for long as the most important pathological feature in AD. These plaques consist of aggregated amyloid- -peptide deposits, -protein aggregation, oxidative stress, dyshomeostasis of biometals, and low acetylcholine (ACh) levels and plays significant role in the pathophysiology of the disease [7]. Nowadays, the most used therapeutic treatment against AD involves the use of acetylcholinesterase inhibitors (AChEIs) that improve AD symptoms by AChE inhibition [8–12]. The reversible AChE inhibition has become the promising target for the treatment of AD which is mainly associated with low in vivo AChE levels. But due to
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