In silico Approach for Anti-Thrombosis Drug Discovery: P2Y1R Structure-Based TCMs Screening

Abstract

Cardiovascular diseases (CVDs), including thrombosis, which is induced by platelet aggregation, are the leading cause of mortality worldwide. The P2Y1 receptor (P2Y1R) facilitates platelet aggregation and is thus an important potential anti-thrombotic drug target. The P2Y1R protein structure contains a binding site for receptor antagonist MRS2500 within its seven-transmembrane bundle, which also provides suitable pockets for numerous other ligands to act as nucleotide antagonists of P2Y1R. The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) comprises 499 Chinese Pharmacopoeia-registered herbs and the structure information for 29,384 ingredients. In silico docking of these compounds into the P2Y1R protein structure within the MRS2500 pocket can identify potential antithrombotic drugs from natural medicinal plants. Docking studies were performed and scored to evaluate ligand-binding affinities. In this study, a total of 8987 compounds from Traditional Chinese Medicine (TCM) were filtered by Lipinski's rule of five, and their ideal oral-intake properties were evaluated. Of these, 1656 compounds distributed in 443 herbs docked into the P2Y1R-MRS2500 structure in 16,317 poses. A total of 38 compounds were ranked with a DockScore above 70, and these may have significant potential for development into anti-thrombosis drugs. These computational results suggested that licorice (Glycyrrhiza uralensis Fisch), cimicifugae (Cimicifuga foetida L.), and ganoderma (Ganoderma lucidum Karst) and their chemical constituents, which have not previously been widely used for anti-thrombosis, may have unexpected effects on platelet aggregation. Moreover, two types of triterpene scaffolds summarized from 10 compounds were distributed in these three herbs and also docked into P2Y1R. These scaffold structures may be utilized for the development of drugs to inhibit platelet aggregation.

Aqueous Extract of Black Maca Prevents Metabolism Disorder via Regulating the Glycolysis/Gluconeogenesis-TCA Cycle and PPARα Signaling Activation in Golden Hamsters Fed a High-Fat, High-Fructose Diet

“…When PharmaDB was used, the chemical structures were prepared in SD format and converted from a 2D cdx file format to 3D models using Open Babel GUI version 2.3.2 (OpenBableGUI; Chris Morley, United States). Molecular energy was minimized using the Energy Minimization module of Discovery Studio version 4.5 (DS 4.5; Accelrys Inc., San Diego, CA, United States) under the Chemistry at Harvard Macromolecular Mechanics (CHARMM) force field ( Yi et al, 2016 ). All pharmacophore models with the shape of the binding pocket were selected for virtual screening using the default settings of the Ligand Profiler module of DS 4.5.…”

In silico approach in reveal traditional medicine plants pharmacological material basis

“…In recent years, with an increasingly in-depth understanding of the structure and function of compounds, a series of new technologies and methods have been applied to the development of medicinal plants [ 4 ]. If we can establish a quick and convenient pathway by which to first accurately predict a large number of chemical compounds and then, based on these results, perform in vivo and in vitro pharmacological experiments for verification, this procedure will significantly improve the efficiency of evaluating the chemical activities of medicinal plants [ 5 ].…”

Neuraminidase Inhibitory Activity and Constituent Characterization of Fagopyrum dibotrys

“…UHPLC-Q-Exactive Orbitrap high resolution mass spectrometry (HRMS) can rapidly detect hundreds of components in complex compound mixtures from plants with short running times [9]. Similarly, molecular docking is a reliable and efficient tool for discovering or designing novel drugs used to screen biological chemical compounds [10,11,12,13]. In the present work (see Figure 1 for a flowchart of the protocol used), four F. dibotrys extracts (ethyl acetate (EA), petroleum ether (P), ethanol (E), and water (W)) were explored in a neuraminidase (NA) activity assay, with the components of the best extract being further identified by UHPLC-Q-Exactive Orbitrap HRMS.…”