A strategy to find novel candidate anti-Alzheimer’s disease drugs by constructing interaction networks between drug targets and natural compounds in medical plants

Abstract

BackgroundAlzheimer’ disease (AD) is an ultimately fatal degenerative brain disorder that has an increasingly large burden on health and social care systems. There are only five drugs for AD on the market, and no new effective medicines have been discovered for many years. Chinese medicinal plants have been used to treat diseases for thousands of years, and screening herbal remedies is a way to develop new drugs.MethodsWe used molecular docking to screen 30,438 compounds from Traditional Chinese Medicine (TCM) against a comprehensive list of AD target proteins. TCM compounds in the top 0.5% of binding affinity scores for each target protein were selected as our research objects. Structural similarities between existing drugs from DrugBank database and selected TCM compounds as well as the druggability of our candidate compounds were studied. Finally, we searched the CNKI database to obtain studies on anti-AD Chinese plants from 2007 to 2017, and only clinical studies were included.ResultsA total of 1,476 compounds (top 0.5%) were selected as drug candidates. Most of these compounds are abundantly found in plants used for treating AD in China, especially the plants from two genera Panax and Morus. We classified the compounds by single target and multiple targets and analyzed the interactions between target proteins and compounds. Analysis of structural similarity revealed that 17 candidate anti-AD compounds were structurally identical to 14 existing approved drugs. Most of them have been reported to have a positive effect in AD. After filtering for compound druggability, we identified 11 anti-AD compounds with favorable properties, seven of which are found in anti-AD Chinese plants. Of 11 anti-AD compounds, four compounds 5,862, 5,863, 5,868, 5,869 have anti-inflammatory activity. The compound 28,814 mainly has immunoregulatory activity. The other six compounds have not yet been reported for any biology activity at present.DiscussionNatural compounds from TCM provide a broad prospect for the screening of anti-AD drugs. In this work, we established networks to systematically study the connections among natural compounds, approved drugs, TCM plants and AD target proteins with the goal of identifying promising drug candidates. We hope that our study will facilitate in-depth research for the treatment of AD in Chinese medicine.

Exploring African Medicinal Plants for Potential Anti-Diabetic Compounds with the DIA-DB Inverse Virtual Screening Web Server

“…The docking scores of the crystallized ligands ranged from −11.3 to −5.7 kcal/mol, and in some cases, the test compounds had better docking scores than the docking scores for the crystallized ligands (Table 1). A docking cutoff score of −9 kcal/mol was set, as it was deemed a reasonable average docking score that covered the top 10%–20% of the test compounds for each protein target [11,12,13].…”

“…A hierarchical clustering analysis of the compounds identified in each protein target group was performed using Tanimoto similarities to identify whether any compounds showed some similar molecular features [11,12,13] (Figure S2). From these clustering results, the maximum common substructure (MCS) analysis was performed in an attempt to identify any potential scaffolds important for predicting the potential activity within the largest cluster group identified (Table 3).…”

“…A Tanimoto similarity analysis was performed to determine whether any similar molecular features occurred between the natural compounds and known/experimental anti-diabetic drugs [11,12,13]. As seen in Figure 4, only a small portion (approximately 10%) of the predicted active compounds showed some similarity with the known anti-diabetic drugs.…”

“…The oral bioavailability, as well as some ADMET parameters, were evaluated for each of the compounds. These are not only important parameters to evaluate for further drug development [11,12,13], but considering that in some areas where easy access to anti-diabetic medication is not always a possibility, an important way for patients to receive some form of anti-diabetic treatment would be through the use of a decoction from a medicinal plant having anti-diabetic properties. Therefore, factors such as the aqueous solubility and oral bioavailability of the bioactive compounds would be of great importance.…”

“…As plants are complex mixtures of several different compounds, with in silico virtual screening methods, hundreds of compounds can be screened against multiple diabetes targets rapidly and cost effectively. This strategy has been employed to identify anti-cancer, anti-stroke, and anti-Alzheimer’s compounds from traditional Chinese medicines, as well as their potential mechanisms of action [11,12,13]. In this study, we have implemented similar in silico methodologies to identify novel African medicinal plants as rich sources of compounds with potential anti-diabetic activity.…”