Abstract
Based on compelling experimental and clinical evidence, Ginkgo biloba L. exerts a beneficial effect in ameliorating mild to moderate dementia in patients with Alzheimer’s disease (AD) and other neurological disorders, although the pharmacological mechanisms remain unknown. In the present study, compounds, their putative target proteins identified using an inverse docking approach, and clinically tested AD-related target proteins were systematically integrated together with applicable bioinformatics methods in silico. The results suggested that the beneficial effects of G. biloba on AD may be contributed by the regulation of hormone sensitivity, improvements in endocrine homeostasis, maintenance of endothelial microvascular integrity, and proteolysis of tau proteins, particularly prior to amyloid β-protein (Aβ) plaque formation. Moreover, we identified six putative protein targets that are significantly related to AD, but have not been researched or have had only preliminary studies conducted on the anti-AD effects of G. biloba. These mechanisms and protein targets are very significant for future scientific research. In addition, the existing mechanisms were also verified, such as the reduction of oxidative stress, anti-apoptotic effects, and protective effects against amyloidogenesis and Aβ aggregation. The discoveries summarized here may provide a macroscopic perspective that will improve our understanding of the molecular mechanism of medicinal plants or dietary supplements, as well as new clues for the future development of therapeutic strategies for AD.
Highlights
The number of patients with Alzheimer’s disease (AD) is predicted to increase exponentially during the few decades [1]
From the 307 native G. biloba compounds collected from the TCMSP database, 25 compounds were screened by ADME and prepared for further study as the candidate compounds as shown in Figure 2 and Supplementary Materials Table S1
The top 10 putative target proteins associated with AD, in turn, were nitric oxide synthase (NOS3), neprilysin (NEP), beta-secretase 1 (BACE1), estrogen receptor (ESR1), amine oxidase B (MAOB), prothrombin (F2), serum albumin (ALB), transthyretin (TTR), matrix metalloproteinase-3 (MMP3), and interleukin-2 (IL2)
Summary
The number of patients with Alzheimer’s disease (AD) is predicted to increase exponentially during the few decades [1]. The inverse docking approach has been developed and used to facilitate the discovery of new drugs [6]. PharmMapper is a web server used to identify potential drug targets through inverse docking by matching the query compound to an in-house pharmacophore model database, with 23,236 proteins covering 16,159 druggable pharmacophore models and 51,431 ligandable pharmacophore models, as of January 2018 [7]. We extensively employ currently available public databases and integrated bioinformatics methodologies and the inverse docking approach to describe a novel paradigm for constructing interpretable networks. This might enable us to reveal the pharmacological mechanism of G. biloba in its beneficial effects on AD
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