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Background: Alzheimer’s disease (AD) is a neurodegenerative condition and the most common type of dementia among the elderly. The enzymes acetylcholinesterase (AChE) and nitric oxide synthase (NOS) have a pivotal role in the pathophysiology of this disease. Objective: This study aimed to select medicinal plant-derived molecules with reported inhibition of AChE and design optimized molecules that could inhibit not only AChE, but also NOS, potentially increasing its efficacy against AD. Methods: 24 compounds were selected from the literature based on their known AChE inhibitory activity. Then, we performed molecular orbital calculations, maps of electrostatic potential, molecular docking study, identification of the pharmacophoric pattern, evaluation of pharmacokinetic and Toxicological Properties of these molecules. Next, ten analogs were generated for each molecule to optimize their effect where the best molecules of natural products had failed. Results: The most relevant correlation was between HOMO and GAP in the correlation matrix of the molecules’ descriptors. The pharmacophoric group’s derivation found these pharmacophoric features: two hydrogen bond acceptors and one aromatic ring. The studied molecules interacted with the active site of AChE through hydrophobic and hydrogen bonds and with NOS through hydrogen interactions only but in a meaningful manner. In the pharmacokinetic and toxicological prediction, the compounds showed satisfactory results. Conclusion: The design of natural products analogs demonstrated good affinities with the pharmacological targets AChE and NOS, with satisfactory pharmacokinetics and toxicology profiles. Thus, the results could identify promising molecules in treating Alzheimer’s disease.
Background: Alzheimer’s disease (AD) is a neurodegenerative condition and the most common type of dementia among the elderly. The enzymes acetylcholinesterase (AChE) and nitric oxide synthase (NOS) have a pivotal role in the pathophysiology of this disease. Objective: This study aimed to select medicinal plant-derived molecules with reported inhibition of AChE and design optimized molecules that could inhibit not only AChE, but also NOS, potentially increasing its efficacy against AD. Methods: 24 compounds were selected from the literature based on their known AChE inhibitory activity. Then, we performed molecular orbital calculations, maps of electrostatic potential, molecular docking study, identification of the pharmacophoric pattern, evaluation of pharmacokinetic and Toxicological Properties of these molecules. Next, ten analogs were generated for each molecule to optimize their effect where the best molecules of natural products had failed. Results: The most relevant correlation was between HOMO and GAP in the correlation matrix of the molecules’ descriptors. The pharmacophoric group’s derivation found these pharmacophoric features: two hydrogen bond acceptors and one aromatic ring. The studied molecules interacted with the active site of AChE through hydrophobic and hydrogen bonds and with NOS through hydrogen interactions only but in a meaningful manner. In the pharmacokinetic and toxicological prediction, the compounds showed satisfactory results. Conclusion: The design of natural products analogs demonstrated good affinities with the pharmacological targets AChE and NOS, with satisfactory pharmacokinetics and toxicology profiles. Thus, the results could identify promising molecules in treating Alzheimer’s disease.
Background: Alzheimer's disease is a progressive neurodegenerative process of multifactorial characteristics. This disease follows the natural aging process, affecting mainly people over 65 years. Pharmacotherapeutic treatment currently combats symptoms related to cognitive function. Several targets begin to attract the interest of the scientific community to develop new drug candidates, which have better pharmacokinetic and lower toxicity parameters. Objective: The present study aims to design new candidates for acetylcholinesterase/β-secretase (AChE/BACE1) multitarget inhibitor drugs. Method: 17 natural products were selected from the literature with anticholinesterase activity and 1 synthetic molecule with inhibitory activity for BACE1. Subsequently, the molecular docking study was performed, followed by the derivation of the pharmacophoric pattern and prediction of pharmacokinetic and toxicological properties. Finally, the hybrid prototype was designed. Results: All selected molecules showed interactions with their respective target enzymes. Derivation of the pharmacophoric pattern from molecules that interacted with the AChE enzyme resulted in 3 pharmacophoric regions: an aromatic ring, an electron-acceptor region and a hydrophobic region. The molecules showed good pharmacokinetic and toxicological results, showing no warnings of mutagenicity and/or carcinogenicity. After the hybridization process, three hybrid molecules were obtained, which showed inhibitory activity for both targets. Conclusion: It is concluded that research in the field of medicinal chemistry is advancing towards the discovery of new drug candidates that bring a better quality of life to patients with AD.
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