Molecular Docking-assisted Protein Chip Screening of Inhibitors for Bcl-2 Family Protein-protein Interaction to Discover Anticancer Agents by Fragment-based Approach

2019 ◽  
Vol 13 (3) ◽  
pp. 260-268 ◽  
Author(s):  
Myoung-Schook Yoou ◽  
Sungjoon Cho ◽  
Youngjin Choi
Keyword(s):  
Molecular Docking ◽  
Protein Interaction ◽  
Anticancer Agents ◽  
Protein Chip ◽  
Protein Protein Interaction ◽  
Family Protein

scholarly journals Commercial SARS-CoV-2 Targeted, Protease Inhibitor Focused and Protein–Protein Interaction Inhibitor Focused Molecular Libraries for Virtual Screening and Drug Design

2021 ◽  
Vol 23 (1) ◽  
pp. 393
Author(s):  
Sebastjan Kralj ◽  
Marko Jukič ◽  
Urban Bren
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Drug Design ◽  
Protease Inhibitor ◽  
Protein Interaction ◽  
Filter Design ◽  
Chemical Space ◽  
Analytical Data ◽  
General Reference ◽  
Protein Protein Interaction

Since December 2019, the new SARS-CoV-2-related COVID-19 disease has caused a global pandemic and shut down the public life worldwide. Several proteins have emerged as potential therapeutic targets for drug development, and we sought out to review the commercially available and marketed SARS-CoV-2-targeted libraries ready for high-throughput virtual screening (HTVS). We evaluated the SARS-CoV-2-targeted, protease-inhibitor-focused and protein–protein-interaction-inhibitor-focused libraries to gain a better understanding of how these libraries were designed. The most common were ligand- and structure-based approaches, along with various filtering steps, using molecular descriptors. Often, these methods were combined to obtain the final library. We recognized the abundance of targeted libraries offered and complimented by the inclusion of analytical data; however, serious concerns had to be raised. Namely, vendors lack the information on the library design and the references to the primary literature. Few references to active compounds were also provided when using the ligand-based design and usually only protein classes or a general panel of targets were listed, along with a general reference to the methods, such as molecular docking for the structure-based design. No receptor data, docking protocols or even references to the applied molecular docking software (or other HTVS software), and no pharmacophore or filter design details were given. No detailed functional group or chemical space analyses were reported, and no specific orientation of the libraries toward the design of covalent or noncovalent inhibitors could be observed. All libraries contained pan-assay interference compounds (PAINS), rapid elimination of swill compounds (REOS) and aggregators, as well as focused on the drug-like model, with the majority of compounds possessing their molecular mass around 500 g/mol. These facts do not bode well for the use of the reviewed libraries in drug design and lend themselves to commercial drug companies to focus on and improve.

scholarly journals Photocatalytic Proximity Labelling of MCL-1 by a BH3 Ligand

2019 ◽  
Author(s):  
Hester Beard ◽  
Rachel George ◽  
Andrew Wilson ◽  
Robin Bon
Keyword(s):  
Visible Light ◽  
Dynamic Analysis ◽  
Protein Interaction ◽  
Affinity Purification ◽  
Cysteine Residue ◽  
Tandem Ms ◽  
Dependent Manner ◽  
Protein Protein Interaction ◽  
Apoptotic Protein ◽  
Family Protein

Ligand-directed protein labelling can be used to introduce diverse chemical functionalities onto proteins without the need for incorporation of genetically encoded tags. Here we report a method for the rapid and efficient labelling of a protein using a ruthenium-bipyridyl (Ru(II)(bpy)3) modified peptide designed to mimic an interacting BH3 ligand within a BCL-2 family protein-protein interaction (PPI). Using sub-stoichiometric quantities of (Ru(II)(bpy)3)-modified NOXA-B and irradiation with visible light for 1 minute, the anti-apoptotic protein MCL-1 was photolabelled in a ligand-dependent manner with a variety of functional tags, as determined by in-gel fluorescence, affinity purification, and ESIMS analysis. In contrast with previous reports on Ru(II)(bpy)3-catalysed photolabelling, tandem MS experiments revealed that the dominant labelling occurred on a cysteine residue of MCL-1. Labelling of MCL-1 occurred selectively in mixtures with other proteins, including the structurally related BCL-2 member, BCL-xL. These results improve methodology for proximity-induced photolabelling of proteins, demonstrate the approach is applicable to interfaces that mediate PPIs, and pave the way towards future use of ligand-directed proximity labelling for dynamic analysis of the localisation and interactome of BCL-2 family proteins.<br>

scholarly journals Photocatalytic Proximity Labelling of MCL-1 by a BH3 Ligand

2019 ◽  
Author(s):  
Hester Beard ◽  
Rachel George ◽  
Andrew Wilson ◽  
Robin Bon
Keyword(s):  
Visible Light ◽  
Dynamic Analysis ◽  
Protein Interaction ◽  
Affinity Purification ◽  
Cysteine Residue ◽  
Tandem Ms ◽  
Dependent Manner ◽  
Protein Protein Interaction ◽  
Apoptotic Protein ◽  
Family Protein

Ligand-directed protein labelling can be used to introduce diverse chemical functionalities onto proteins without the need for incorporation of genetically encoded tags. Here we report a method for the rapid and efficient labelling of a protein using a ruthenium-bipyridyl (Ru(II)(bpy)3) modified peptide designed to mimic an interacting BH3 ligand within a BCL-2 family protein-protein interaction (PPI). Using sub-stoichiometric quantities of (Ru(II)(bpy)3)-modified NOXA-B and irradiation with visible light for 1 minute, the anti-apoptotic protein MCL-1 was photolabelled in a ligand-dependent manner with a variety of functional tags, as determined by in-gel fluorescence, affinity purification, and ESIMS analysis. In contrast with previous reports on Ru(II)(bpy)3-catalysed photolabelling, tandem MS experiments revealed that the dominant labelling occurred on a cysteine residue of MCL-1. Labelling of MCL-1 occurred selectively in mixtures with other proteins, including the structurally related BCL-2 member, BCL-xL. These results improve methodology for proximity-induced photolabelling of proteins, demonstrate the approach is applicable to interfaces that mediate PPIs, and pave the way towards future use of ligand-directed proximity labelling for dynamic analysis of the localisation and interactome of BCL-2 family proteins.<br>

scholarly journals Cell Division in genus Corynebacterium: protein-protein interaction and molecular docking of SepF and FtsZ in the understanding of cytokinesis in pathogenic species

2018 ◽  
Vol 90 (2 suppl 1) ◽  
pp. 2179-2188 ◽  
Author(s):  
ALBERTO F. OLIVEIRA JR ◽  
EDSON L. FOLADOR ◽  
ANNE C.P. GOMIDE ◽  
ARISTÓTELES GOES-NETO ◽  
VASCO A.C. AZEVEDO ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cell Division ◽  
Protein Interaction ◽  
Pathogenic Species ◽  
Protein Protein Interaction ◽  
Genus Corynebacterium

scholarly journals Identification of Potential Bioactive Ingredients and Mechanisms of the Guanxin Suhe Pill on Angina Pectoris by Integrating Network Pharmacology and Molecular Docking

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Mingmin Wang ◽  
Shuangjie Yang ◽  
Mingyan Shao ◽  
Qian Zhang ◽  
Xiaoping Wang ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Angina Pectoris ◽  
Protein Interaction ◽  
Interaction Analysis ◽  
Network Pharmacology ◽  
Biological Processes ◽  
Protein Protein Interaction ◽  
Go Enrichment ◽  
Chemokine Ligand ◽  
Bioactive Ingredients

The Guanxin Suhe pill (GSP), a traditional Chinese medicine, has been widely used to treat angina pectoris (AP) in Chinese clinical practice. However, research on the bioactive ingredients and underlying mechanisms of GSP in AP remains scarce. In this study, a system pharmacology approach integrating gastrointestinal absorption (GA) evaluation, drug-likeness (DL) evaluation, target exploration, protein-protein-interaction analysis, Gene Ontology (GO) enrichment analysis, network construction, and molecular docking was adopted to explore its potential mechanisms. A total of 481 ingredients from five herbs were collected, and 242 were qualified based on GA and DL evaluation. Target exploration identified 107 shared targets between GSP and AP. Protein-protein interaction identified VEGFA (vascular endothelial growth factor A), TNF (tumor necrosis factor), CCL2 (C-C motif chemokine ligand 2), FN1 (fibronectin 1), MMP9 (matrix metallopeptidase 9), PTGS2 (prostaglandin-endoperoxide synthase 2), IL10 (interleukin 10), CXCL8 (C-X-C motif chemokine ligand 8), IL6 (interleukin 6), and INS (insulin) as hub targets for GSP, which were involved in the inflammatory process, ECM proteolysis, glucose metabolism, and lipid metabolism. GO enrichment identified top pathways in the biological processes, molecular functions, and cell components, explaining GSP’s potential AP treatment mechanism. Positive regulation of the nitric oxide biosynthetic process and the response to hypoxia ranked highest of the biological processes; core targets that GSP can regulate in these two pathways were PTGS2 and NOS2, respectively. Molecular docking verified the interactions between the core genes in the pathway and the active ingredients. The study lays a foundation for further experimental research and clinical application.

scholarly journals The Mechanism of Compound Anshen Essential Oil in the Treatment of Insomnia Was Examined by Network Pharmacology

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Guilin Ren ◽  
Yu Zhong ◽  
Gang Ke ◽  
Xiaoli Liu ◽  
Huiting Li ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Essential Oil ◽  
Protein Interaction ◽  
Active Component ◽  
Chloride Transport ◽  
Interaction Network ◽  
Binding Activity ◽  
Network Pharmacology ◽  
Protein Protein Interaction ◽  
Target Network

The active component-target network and protein-protein interaction network of Compound Anshen essential oil were constructed. The target functions and related pathways were analyzed to explore the mechanism of Compound Anshen essential oil in the treatment of insomnia. GC-MS was used to detect the chemical composition of Compound Anshen essential oil, and the TCMSP, STITCH, TTD, and DrugBank databases were searched to predict and screen the targets of Compound Anshen essential oil in the treatment of insomnia. Cytoscape software was used to construct the network diagrams of the active component-action target and protein-protein interaction networks, ClueGO software was used to analyze the GO enrichment and KEGG pathway of the target, and the systemsDock website database was used for molecular docking. The analysis of the network results showed that the activity of Compound Anshen essential oil mainly involves biological processes such as the phospholipase C-activating G protein-coupled receptor signaling pathway, response to ammonium ions, calcium ion transport into the cytosol, and chloride transport. The results of molecular docking showed that linalool, caryophyllene, dibutyl phthalate, (-)-4-terpineol, and (-)-α-terpineol have good binding activity with ADRB2, DRD2, ESR1, KCNH2, NR1H4, NR1I2, NR1I3, and TRPV1 targets. This study demonstrates the multicomponent, multitarget, and multichannel characteristics of Compound Anshen essential oil and provides a new therapeutic idea and method for further research on the mechanism of Compound Anshen essential oil in the treatment of insomnia.

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