Insight into Ginkgo biloba L. Extract on the Improved Spatial Learning and Memory by Chemogenomics Knowledgebase, Molecular Docking, Molecular Dynamics Simulation, and Bioassay Validations

Abstract

Epilepsy is a common cause of serious cognitive disorders and is known to have impact on patients’ memory and executive functions. Therefore, the development of antiepileptic drugs for the improvement of spatial learning and memory in patients with epileptic cognitive dysfunction is important. In the present work, we systematically predicted and analyzed the potential effects of Ginkgo terpene trilactones (GTTL) on cognition and pathologic changes utilizing in silico and in vivo approaches. Based on our established chemogenomics knowledgebase, we first conducted the network systems pharmacology analysis to predict that ginkgolide A/B/C may target 5-HT 1A, 5-HT 1B, and 5-HT 2B. The detailed interactions were then further validated by molecular docking and molecular dynamics (MD) simulations. In addition, status epilepticus (SE) was induced by lithium–pilocarpine injection in adult Wistar male rats, and the results of enzyme-linked immunosorbent assay (ELISA) demonstrated that administration with GTTL can increase the expression of brain-derived neurotrophic factor (BDNF) when compared to the model group. Interestingly, recent studies suggest that the occurrence of a reciprocal involvement of 5-HT receptor activation along with the hippocampal BDNF-increased expression can significantly ameliorate neurologic changes and reverse behavioral deficits in status epilepticus rats while improving cognitive function and alleviating neuronal injury. Therefore, we evaluated the effects of GTTL (bilobalide, ginkgolide A, ginkgolide B, and ginkgolide C) on synergistic antiepileptic effect. Our experimental data showed that the spatial learning and memory abilities (e.g., electroencephalography analysis and Morris water maze test for behavioral assessment) of rats administrated with GTTL were significantly improved under the middle dose (80 mg/kg, GTTL) and high dose (160 mg/kg, GTTL). Moreover, the number of neurons in the hippocampus of the GTTL group increased when compared to the model group. Our studies showed that GTTL not only protected rat cerebral hippocampal neurons against epilepsy but also improved the learning and memory ability. Therefore, GTTL may be a potential drug candidate for the prevention and/or treatment of epilepsy.

MCCS: a novel recognition pattern-based method for fast track discovery of anti-SARS-CoV-2 drugs

“…On the basis of our established domain specific chemogenomics databases [ 32–35 ] and our novel computational techniques [ 32 , 36–39 ], we constructed and reported a novel virus-associated disease-specific chemogenomics knowledgebase (Virus-CKB, https://www.cbligand.org/g/virus-ckb ) [ 27 ] and applied our computational systems pharmacology-target mapping (CSP-Target Mapping) to rapidly identify the FDA-approved drugs for repurposing into new indications by fast progress into clinical trials to meet the urgent demand due to the COVID-19 outbreak. Virus-CKB, a one-stop computing platform describes the chemical molecules, genes, proteins and signaling pathways involved in the regulation of virus-associated diseases.…”

“…To date, the Virus-CKB archived 65 antiviral drugs in the market, 107 virus-related proteins or enzymes with 189 available 3D crystal or cryo-EM structures [ 40–42 ], and ~2609 chemical agents reported for these target proteins and enzymes. In addition, the Virus-CKB is implemented with our developed machine-learning computational algorithms and computing tools for the prediction of the important protein targets, and the output data analysis and visualization, including HTDocking [ 32 , 36–38 ], TargetHunter [ 32 , 36–39 ], BBB predictor [ 32 , 37 , 38 ], NGL viewer [ 43 ], Spider Plot [ 32 , 36 , 37 ], etc.…”

Virus-CKB: an integrated bioinformatics platform and analysis resource for COVID-19 research

“…The Virus-CKB server is an integrated web server that combines our established tools and algorithms (HTDocking [ 18–22 ], TargetHunter [ 23 ], blood–brain barrier (BBB) predictor [ 20–22 ] and Spider Plot [ 18 , 19 , 24 ]) and other third-party software (Open Babel [ 25 ], JSME Molecular Editor [ 26 ], idock [ 27 ] and NGL Viewer [ 28 ]) for target identification and network systems pharmacology analysis. The Virus-CKB pipeline is shown in Figure 1 .…”

“…CSP-Target Mapping or Spider Plot [ 18 , 19 , 24 ] is also integrated into Virus-CKB for visualizing the molecule–protein interaction network based on the output of HTDocking and TargetHunter. The detailed information related to Spider Plot can found in our recent publication [ 24 ].…”

The Underlying Molecular Mechanisms Involved in Traditional Chinese Medicine Smilax china L. for the Treatment of Pelvic Inflammatory Disease

“…Because multiple constituents may produce synergistic regulation on different targets, elucidating the mechanisms of TCM always takes lots of time and resources. ere is no doubt that systems pharmacology has recently emerged as a new field including physiology, genetics, biochemistry, and molecular simulation via integrating various research methods to investigate the complicated mechanisms of multiple compounds [18,19]. Nowadays, systems pharmacology has been applied for revealing the pharmacological mechanism of TCM from the perspective of entirety.…”