Structure-based virtual screening of novel, high-affinity BRD4 inhibitors

2014 ◽  
Vol 10 (9) ◽  
pp. 2384 ◽  
Author(s):  
Charuvaka Muvva ◽  
E. R. Azhagiya Singam ◽  
S. Sundar Raman ◽  
V. Subramanian
Keyword(s):  
Virtual Screening ◽  
High Affinity

Discovery of High-Affinity Ligands of σ1Receptor, ERG2, and Emopamil Binding Protein by Pharmacophore Modeling and Virtual Screening

2005 ◽  
Vol 48 (15) ◽  
pp. 4754-4764 ◽  
Author(s):  
Christian Laggner ◽  
Claudia Schieferer ◽  
Birgit Fiechtner ◽  
Gloria Poles ◽  
Rémy D. Hoffmann ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Binding Protein ◽  
Pharmacophore Modeling ◽  
Affinity Ligands ◽  
High Affinity

Virtual Screening of Inhibitors Against Spike Glycoprotein of SARS-CoV-2: A Drug Repurposing Approach

2020 ◽  
Author(s):  
Kanishka Senathilake ◽  
Sameera Samarakoon ◽  
Kamani Tennekoon
Keyword(s):  
Virtual Screening ◽  
Drug Repurposing ◽  
Homology Model ◽  
Respiratory Illness ◽  
Receptor Interaction ◽  
S Protein ◽  
Surface Receptors ◽  
High Affinity ◽  
Food Dye ◽  
Novel Coronavirus

The novel coronavirus (SARS-CoV-2) is a human pathogen recently emerged in China, causing a global pandemic of severe respiratory illness (COVID19). SARS-CoV-2 makes entry into human cells through its spike (S) protein that binds to cell surface receptors. Widespread of SARS-CoV-2 has been attributed to high affinity of S protein to its receptor. A homology model of the receptor binding domain of SARS-CoV-2 S protein (RBD) was built. RBD- receptor docking and published molecular dynamics data were used to map the key RBD-receptor interaction hotspot (RBDhp) on the RBD. Primary virtual screening was carried out against RBDhp using more than 3300 compounds approved by U.S Food and Drug Administration (FDA) and other authorities for human use. Compounds that bind to hpRBD with a binding energy ≤ - 6.5 kcal/mol were subjected to secondary screening using a recently published cryo EM (2.9 Å) structure of RBD. A cardiac glycoside (dgitoxin), two anthracyclines (zorubicin and aclarubicin), a tetracycline derivative (rolitetracycline), a cephalosporin (cefoperazone) and a food dye (E-155) were predicted to be most potent inhibitors of RBD – receptor interaction. An anti-asthmatic drug (zafirlukast) and several other drugs (itrazol, fazadinium, troglitazone, gliquidone, Idarubicin, Oxacillin) were found to be high affinity binders that may have a potential to inhibit RBD – receptor interaction.

scholarly journals Virtual screening for high affinity guests for synthetic supramolecular receptors

2015 ◽  
Vol 6 (5) ◽  
pp. 2790-2794 ◽  
Author(s):  
William Cullen ◽  
Simon Turega ◽  
Christopher A. Hunter ◽  
Michael D. Ward
Keyword(s):  
Virtual Screening ◽  
Ligand Docking ◽  
High Affinity

The protein/ligand docking programme ‘GOLD’ can be used to identify new strongly-binding guests for a synthetic coordination cage host.

scholarly journals COVID-19 Repurposed Therapeutics Targeting the Viral Protease and Spike-protein:ACE2 Interface using MD-based Pharmacophore and Consensus Virtual Screening

2020 ◽  
Author(s):  
brady garabato ◽  
Federico Falchi ◽  
Andrea Cavalli
Keyword(s):  
Molecular Dynamics ◽  
Virtual Screening ◽  
Crystal Structures ◽  
High Throughput ◽  
Binding Energies ◽  
Enhanced Sampling ◽  
Viral Protease ◽  
High Affinity ◽  
Receptor Interface

<p>Molecular dynamics (MD) and enhanced sampling MD was performed for 100 ns on the biological assembly of the COVID-19 protease (<a href="https://www.rcsb.org/structure/6lu7">6LU7</a>), and a template of the COVID-19 S-protein:ACE2 receptor interface (99.88% coverage of 6M0J; model03, <a href="https://swissmodel.expasy.org/interactive/HLkhkP/models/">swissmodel</a>). Apo-site pharmacophores of the resulting structural clusters were used to mine the FDA database (8700 compounds), and a multi-target library was developed from MD-based hits in high affinity sites across 100 ns. Consensus hits from high throughput docking in crystal structures 5R82, 6LU7 and 6Y2F (protease), and 6VW1 (S-protein:ACE2) were also added, and the resulting libraries were re-docked into MD sites to collect potential COVID-19 re-purposed therapeutics by estimated binding energies. </p>

scholarly journals Virtual screening identifies novel high-affinity σ1 receptor ligands

2019 ◽  
Author(s):  
Daniel A. Greenfield ◽  
Hayden R. Schmidt ◽  
Piotr Sliz ◽  
Andrew C. Kruse
Keyword(s):  
Virtual Screening ◽  
High Throughput ◽  
Transmembrane Protein ◽  
Cross Reactivity ◽  
Receptor Ligands ◽  
Computational Docking ◽  
High Affinity ◽  
Σ1 Receptor ◽  
Ligand Discovery

AbstractThe σ1 receptor is a transmembrane protein implicated in several pathophysiological conditions, including neurodegenerative disease1, drug addiction2, cancer3, and pain4. However, there are no high-throughput functional assays for σ1 receptor drug discovery. Here, we assessed high-throughput structure-based computational docking for discovery of novel ligands of the σ1 receptor. We screened a library of over 6 million compounds using the Schrödinger Glide package, followed by experimental characterization of top-scoring candidates. 77% of tested candidates bound σ1 with high affinity (10-550 nM). These include compounds with high selectivity for the σ1 receptor compared to the genetically unrelated but pharmacologically similar σ2 receptor, as well as compounds with substantial cross-reactivity between the two receptors. These results establish structure-based virtual screening as a highly effective platform for σ1 receptor ligand discovery.

scholarly journals COVID-19 Repurposed Therapeutics Targeting the Viral Protease and Spike-protein:ACE2 Interface using MD-based Pharmacophore and Consensus Virtual Screening

2020 ◽  
Author(s):  
brady garabato ◽  
Federico Falchi ◽  
Andrea Cavalli
Keyword(s):  
Molecular Dynamics ◽  
Virtual Screening ◽  
Crystal Structures ◽  
High Throughput ◽  
Binding Energies ◽  
Enhanced Sampling ◽  
Viral Protease ◽  
High Affinity ◽  
Receptor Interface

<p>Molecular dynamics (MD) and enhanced sampling MD was performed for 100 ns on the biological assembly of the COVID-19 protease (<a href="https://www.rcsb.org/structure/6lu7">6LU7</a>), and a template of the COVID-19 S-protein:ACE2 receptor interface (99.88% coverage of 6M0J; model03, <a href="https://swissmodel.expasy.org/interactive/HLkhkP/models/">swissmodel</a>). Apo-site pharmacophores of the resulting structural clusters were used to mine the FDA database (8700 compounds), and a multi-target library was developed from MD-based hits in high affinity sites across 100 ns. Consensus hits from high throughput docking in crystal structures 5R82, 6LU7 and 6Y2F (protease), and 6VW1 (S-protein:ACE2) were also added, and the resulting libraries were re-docked into MD sites to collect potential COVID-19 re-purposed therapeutics by estimated binding energies. </p>

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