scholarly journals p38α MAPK and Type I Inhibitors: Binding Site Analysis and Use of Target Ensembles in Virtual Screening

Molecules ◽  
2015 ◽  
Vol 20 (9) ◽  
pp. 15842-15861 ◽  
Author(s):  
Andrea Astolfi ◽  
Nunzio Iraci ◽  
Stefano Sabatini ◽  
Maria Barreca ◽  
Violetta Cecchetti
Keyword(s):  
Virtual Screening ◽  
Binding Site ◽  
Type I ◽  
Site Analysis ◽  
P38α Mapk

scholarly journals Large-Scale Virtual Screening Against the MET Kinase Domain Identifies a New Putative Inhibitor Type

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 938 ◽  
Author(s):  
Emmanuel Bresso ◽  
Alessandro Furlan ◽  
Philippe Noel ◽  
Vincent Leroux ◽  
Flavio Maina ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Binding Site ◽  
Large Scale ◽  
Cost Effective ◽  
Kinase Domain ◽  
Functional Method ◽  
Conformational Space ◽  
Classical Type ◽  
Type I ◽  
Ensemble Docking

By using an ensemble-docking strategy, we undertook a large-scale virtual screening campaign in order to identify new putative hits against the MET kinase target. Following a large molecular dynamics sampling of its conformational space, a set of 45 conformers of the kinase was retained as docking targets to take into account the flexibility of the binding site moieties. Our screening funnel started from about 80,000 chemical compounds to be tested in silico for their potential affinities towards the kinase binding site. The top 100 molecules selected—thanks to the molecular docking results—were further analyzed for their interactions, and 25 of the most promising ligands were tested for their ability to inhibit MET activity in cells. F0514-4011 compound was the most efficient and impaired this scattering response to HGF (Hepatocyte Growth Factor) with an IC 50 of 7.2 μ M. Interestingly, careful docking analysis of this molecule with MET suggests a possible conformation halfway between classical type-I and type-II MET inhibitors, with an additional region of interaction. This compound could therefore be an innovative seed to be repositioned from its initial antiviral purpose towards the field of MET inhibitors. Altogether, these results validate our ensemble docking strategy as a cost-effective functional method for drug development.

Comprehensive in silico Study of GLUT10: Prediction of Possible Substrate Binding Sites and Interacting Molecules

2020 ◽  
Vol 21 (2) ◽  
pp. 117-130 ◽  
Author(s):  
Mohammad J. Hosen ◽  
Mahmudul Hasan ◽  
Sourav Chakraborty ◽  
Ruhshan A. Abir ◽  
Abdullah Zubaer ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Binding Site ◽  
Glucose Transporter ◽  
Substrate Binding ◽  
Mutation Screening ◽  
Homology Model ◽  
Connective Tissue Disorder ◽  
Crystallographic Structure ◽  
Substrate Binding Site

Objectives: The Arterial Tortuosity Syndrome (ATS) is an autosomal recessive connective tissue disorder, mainly characterized by tortuosity and stenosis of the arteries with a propensity towards aneurysm formation and dissection. It is caused by mutations in the SLC2A10 gene that encodes the facilitative glucose transporter GLUT10. The molecules transported by and interacting with GLUT10 have still not been unambiguously identified. Hence, the study attempts to identify both the substrate binding site of GLUT10 and the molecules interacting with this site. Methods: As High-resolution X-ray crystallographic structure of GLUT10 was not available, 3D homology model of GLUT10 in open conformation was constructed. Further, molecular docking and bioinformatics investigation were employed. Results and Discussion: Blind docking of nine reported potential in vitro substrates with this 3D homology model revealed that substrate binding site is possibly made with PRO531, GLU507, GLU437, TRP432, ALA506, LEU519, LEU505, LEU433, GLN525, GLN510, LYS372, LYS373, SER520, SER124, SER533, SER504, SER436 amino acid residues. Virtual screening of all metabolites from the Human Serum Metabolome Database and muscle metabolites from Human Metabolite Database (HMDB) against the GLUT10 revealed possible substrates and interacting molecules for GLUT10, which were found to be involved directly or partially in ATS progression or different arterial disorders. Reported mutation screening revealed that a highly emergent point mutation (c. 1309G>A, p. Glu437Lys) is located in the predicted substrate binding site region. Conclusion: Virtual screening expands the possibility to explore more compounds that can interact with GLUT10 and may aid in understanding the mechanisms leading to ATS.

scholarly journals Biochemical and structural characterization of the novel sialic acid-binding site of Escherichia coli heat-labile enterotoxin LT-IIb

2016 ◽  
Vol 473 (21) ◽  
pp. 3923-3936 ◽  
Author(s):  
Dani Zalem ◽  
João P. Ribeiro ◽  
Annabelle Varrot ◽  
Michael Lebens ◽  
Anne Imberty ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Binding Site ◽  
Cholera Toxin ◽  
Carbohydrate Binding ◽  
Type I ◽  
Type Ii ◽  
E Coli ◽  
B Subunit ◽  
Heat Labile ◽  
B Subunits

The structurally related AB5-type heat-labile enterotoxins of Escherichia coli and Vibrio cholerae are classified into two major types. The type I group includes cholera toxin (CT) and E. coli LT-I, whereas the type II subfamily comprises LT-IIa, LT-IIb and LT-IIc. The carbohydrate-binding specificities of LT-IIa, LT-IIb and LT-IIc are distinctive from those of cholera toxin and E. coli LT-I. Whereas CT and LT-I bind primarily to the GM1 ganglioside, LT-IIa binds to gangliosides GD1a, GD1b and GM1, LT-IIb binds to the GD1a and GT1b gangliosides, and LT-IIc binds to GM1, GM2, GM3 and GD1a. These previous studies of the binding properties of type II B-subunits have been focused on ganglio core chain gangliosides. To further define the carbohydrate binding specificity of LT-IIb B-subunits, we have investigated its binding to a collection of gangliosides and non-acid glycosphingolipids with different core chains. A high-affinity binding of LT-IIb B-subunits to gangliosides with a neolacto core chain, such as Neu5Gcα3- and Neu5Acα3-neolactohexaosylceramide, and Neu5Gcα3- and Neu5Acα3-neolactooctaosylceramide was detected. An LT-IIb-binding ganglioside was isolated from human small intestine and characterized as Neu5Acα3-neolactohexaosylceramide. The crystal structure of the B-subunit of LT-IIb with the pentasaccharide moiety of Neu5Acα3-neolactotetraosylceramide (Neu5Ac-nLT: Neu5Acα3Galβ4GlcNAcβ3Galβ4Glc) was determined providing the first information for a sialic-binding site in this subfamily, with clear differences from that of CT and LT-I.

Identification of Bilirubin Binding Site in Type I Collagen

2013 ◽  
Vol 19 (4) ◽  
pp. 357-364 ◽  
Author(s):  
Nagarajan Usharani ◽  
Gladstone Christopher Jayakumar ◽  
Swarna V. Kanth ◽  
Jonnalagadda Raghava Rao ◽  
Bangaru Chandrasekaran ◽  
...  
Keyword(s):  
Binding Site ◽  
Type I Collagen ◽  
Type I ◽  
Bilirubin Binding

The C-terminus type I collagen is a major binding site for heparin

1986 ◽  
Vol 882 (1) ◽  
pp. 1-5 ◽  
Author(s):  
Katharyn M. Keller ◽  
John M. Keller ◽  
Klaus Kühn
Keyword(s):  
Binding Site ◽  
Type I Collagen ◽  
Type I ◽  
C Terminus

Virtual screening using a conformationally flexible target protein: models for ligand binding to p38α MAPK

2012 ◽  
Vol 26 (4) ◽  
pp. 409-423 ◽  
Author(s):  
Natalie B. Vinh ◽  
Jamie S. Simpson ◽  
Peter J. Scammells ◽  
David K. Chalmers
Keyword(s):  
Virtual Screening ◽  
Ligand Binding ◽  
Target Protein ◽  
P38α Mapk ◽  
Protein Models
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