Abstract
Alzheimer's disease (AD) is characterized by the progressive disturbance in cognition and affects approximately 36 million people, worldwide. However, the drugs used to treat this disease are only moderately effective and do not alter the course of the neurodegenerative process. This is because the pathogenesis of AD is mainly associated with oxidative stress, and current drugs only target two enzymes involved in neurotransmission. Therefore, the present study sought to identify potential multitarget compounds for enzymes that are directly or indirectly involved in the oxidative pathway, with minimal side effects, for AD treatment. A set of 159 lignans were submitted to studies of QSAR and molecular docking. A combined analysis was performed, based on ligand and structure, followed by the prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. The results showed that the combined analysis was able to select 139 potentially active and multitarget lignans targeting two or more enzymes, among them are c-Jun N-terminal kinase 3 (JNK-3), protein tyrosine phosphatase 1B (PTP1B), nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1), NADPH quinone oxidoreductase 1 (NQO1), phosphodiesterase 5 (PDE5), nuclear factor erythroid 2-related factor 2 (Nrf2), cycloxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS). The authors conclude that compounds (06) austrobailignan 6, (11) anolignan c, (19) 7-epi-virolin, (64) 6-[(2R,3R,4R,5R)-3,4-dimethyl-5-(3,4,5-trimethoxyphenyl)oxolan-2-yl]-4-methoxy-1,3-benzodioxole, (116) ococymosin, and (135) mappiodoinin b have probabilities that confer neuroprotection and antioxidant activity and represent potential alternative AD treatment drugs or prototypes for the development of new drugs with anti-AD properties.
Highlights
Alzheimer’s disease is a multifactorial disease [1, 2], it is characterized by the increased generation and/or accumulation of amyloidogenic peptides ( Aβ), which are derived from the proteolysis of amyloid precursor protein (APP) [3]
The metrics mentioned are the most commonly used metrics for chemoinformatics, others can be used to guarantee the high predictability of the model, such as receiver operating characters (ROC) curves [120]
The results showed that the targets Jun N-terminal kinase 3 (JNK-3), protein tyrosine phosphatase 1B (PTP1B), Nicotinamide Adenine Dinucleotide Phosphate (NADPH) quinone oxidoreductase 1 (NQO1), phosphodiesterase 5 (PDE5), cycloxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS) obtained root-meansquare deviation (RMSD) values of 0.56, 0.25, 0.18, 0.47, 0.19, and 0.16 Å, respectively
Summary
Alzheimer’s disease is a multifactorial disease [1, 2], it is characterized by the increased generation and/or accumulation of amyloidogenic peptides ( Aβ), which are derived from the proteolysis of APP [3]. The presence of senile plaques in the cerebral cortex is thought to result in the activation of inflammatory and neurotoxic processes, culminating in the production of NO, cytokines, and ROS [3,4,5,6,7,8,9]. This process contributes to neurodegeneration and the loss of neuronal cells in AD [10, 11]. ROS can have beneficial and negative effects on cellular functions, depending on their concentrations. Oxidative stress is at the heart of AD pathogenesis [12, 13]
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