Combined network pharmacology and virtual reverse pharmacology approaches for identification of potential targets to treat vascular dementia

Abstract

Dementia is a major cause of disability and dependency among older people. if the lives of people with dementia are to be improved, research and its translation into druggable target are crucial. Ancient systems of healthcare (Ayurveda, Siddha, Unani and Sowa-Rigpa) have been used from centuries for the treatment vascular diseases and dementia. this traditional knowledge can be transformed into novel targets through robust interplay of network pharmacology (NetP) with reverse pharmacology (RevP), without ignoring cutting edge biomedical data. This work demonstrates interaction between recent and traditional data, and aimed at selection of most promising targets for guiding wet lab validations. PROTEOME, DisGeNE, DISEASES and DrugBank databases were used for selection of genes associated with pathogenesis and treatment of vascular dementia (VaD). The selection of new potential drug targets was made by methods of NetP (DIAMOnD algorithm, enrichment analysis of KEGG pathways and biological processes of Gene Ontology) and manual expert analysis. The structures of 1976 phytomolecules from the 573 Indian medicinal plants traditionally used for the treatment of dementia and vascular diseases were used for computational estimation of their interactions with new predicted VaD-related drug targets by RevP approach based on PASS (Prediction of Activity Spectra for Substances) software. We found 147 known genes associated with vascular dementia based on the analysis of the databases with gene-disease associations. Six hundred novel targets were selected by NetP methods based on 147 gene associations. The analysis of the predicted interactions between 1976 phytomolecules and 600 NetP predicted targets leaded to the selection of 10 potential drug targets for the treatment of VaD. The translational value of these targets is discussed herewith. Twenty four drugs interacting with 10 selected targets were identified from DrugBank. These drugs have not been yet studied for the treatment of VaD and may be investigated in this field for their repositioning. The relation between inhibition of two selected targets (GSK-3, PTP1B) and the treatment of VaD was confirmed by the experimental studies on animals and reported separately in our recent publications.Dementia is a group of neurological diseases that usually occur in old age and are characterized by a progressive loss of cognitive function, leading to deterioration in social and professional abilities associated with memory loss, learning, communication, and reasoning. Ten million people develop dementia every year. According to Global Dementia Observatory (GDB) the number of people with dementia will increase from 50 million to 152 million by 2050. It is expected that the annual global cost of dementia will be doubled by 2030 up to US$ 2 trillion 1 .

The Material Basis and Mechanism of Xuefu Zhuyu Decoction in Treating Stable Angina Pectoris and Unstable Angina Pectoris

“…Based on the research idea of network pharmacology, we can calculate and compare the mechanism of action of this formula for treating two types of angina pectoris from a systematic, holistic, and modular perspective, by constructing the complex networks [ 14 , 15 ]. In contrast to forward network pharmacology, the reverse network pharmacology approach allows for the reverse access to the targets and components at play in the complex networks constructed from the perspective of disease characterization and function [ 16 ]. The strength of binding of a compound to different targets can be expressed in terms of the results of molecular docking [ 17 , 18 ].…”

Low-dose Drosera rotundifolia induces gene expression changes in 16HBE human bronchial epithelial cells

“…This study shows that a diluted herbal extract used in a traditional homeopathic pharmacopoeia 5 , 9 – 12 can induce a change in mRNA expression that can be measured reliably and reproducibly. Low doses of traditional plants and homeopathic dilutions are now being investigated by means of molecular biology techniques for differential gene expression analysis and bioinformatics 24 – 28 .…”

In silico Methods for Identification of Potential Therapeutic Targets

“…For example, it may be an essential protein for pathogen survival and thus identified as a potential therapeutic target [8]. However, centrality sometimes cannot be applied directly to normal human protein networks because of the toxicity of acting on such critical nodes [10,25]. To solve this problem, the direct screening and elimination process of homologous proteins involved in metabolism can be complemented with differential network analysis in which two or more networks are compared, such as normal cell and disease (mostly cancer) cell networks, different subtype networks of cancer, and tissue-specific networks.…”