Design of Multitarget Natural Products Analogs with Potential Anti-Alzheimer’s Activity

Franciane   Nunes   de Souza; Henrique   Barros   de Lima; Lucilene   Rocha   de Souza; Gabrieli   Santos   Oliveira; Carlos   Henrique Tomich   de Paula da Silva; Arlindo   César Matias   Pereira; Lorane   Izabel   da Silva Hage-Melim

doi:10.2174/1573409918666220328141605

Abstract

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 the following 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 for treating Alzheimer’s disease.

Keywords: Alzheimer's disease, acetylcholinesterase, nitric oxide synthase, natural products, correlation matrix, NOS.

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DOI https://dx.doi.org/10.2174/1573409918666220328141605	Print ISSN 1573-4099
Publisher Name Bentham Science Publisher	Online ISSN 1875-6697

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