Abstract
The aim of this study was to identify new potentially active compounds for three protein targets, tropomyosin receptor kinase A (TrkA), N-methyl-d-aspartate (NMDA) receptor, and leucine-rich repeat kinase 2 (LRRK2), that are related to various neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and neuropathic pain. We used a combination of machine learning methods including artificial neural networks and advanced multilinear techniques to develop quantitative structure–activity relationship (QSAR) models for all target proteins. The models were applied to screen more than 13,000 natural compounds from a public database to identify active molecules. The best candidate compounds were further confirmed by docking analysis and molecular dynamics simulations using the crystal structures of the proteins. Several compounds with novel scaffolds were predicted that could be used as the basis for development of novel drug inhibitors related to each target.
Highlights
A natural product (NP) is generally defined as a chemical compound or substance that is produced by living organisms
leucine-rich repeat kinase 2 (LRRK2) and 40 for tropomyosin receptor kinase A (TrkA) were studied by molecular docking
The results were compared with the modeling data on known NMDA, LRRK2, and TrkA inhibitors
Summary
A natural product (NP) is generally defined as a chemical compound or substance that is produced by living organisms. The use of natural products as medicines has been described throughout human history in terms of substances related to herbal medicines, potions, oils, remedies, and foods. Many of these substances have been discovered by trial and error, and through the years they have become standard products in human lives [1,2]. Development efforts in NP drug discovery have demonstrated a certain downturn in recent years [3] Despite this decline, the vast chemical space of natural products continues to provide abundant structural diversity for discovering novel lead compounds with low molecular weight. Numerous lead NPs that may be used against a broad spectrum of diseases await discovery
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