Identification of Novel c-Yes Kinase Inhibitors
03 Aug 2014-pp 494-500
TL;DR: High throughput virtual screening and docking methods were employed to identify novel inhibitors of c-Yes tyrosine kinase for further development of potent drugs to treat colorectal cancer.
Abstract: c-Yes is a member of Src tyrosine kinase family and it is over expressed in human colorectal cancer cells. c-Yes tyrosine kinase is an attractive target due to its inhibition controls colon tumorigenesis, metastasis and angiogenesis. High throughput virtual screening and docking methods were employed to identify novel inhibitors based on the three dimensional structure of c-Yes. Kinase domain of c-Yes is modelled with reference to the crystal structure available for Src kinase structure and simulated for 100 ns to obtain ensembles with distinct conformation of the active site. Seven ensembles obtained from molecular dynamics (MD) trajectory and one homology model were used to screen library of the 2 million Enamine HTS compounds. A library of 159 Src kinase inhibitors and 6319 associated decoys is used for validation. Based on the score values, 25 compounds were shortlisted and reported as novel inhibitors of c-Yes kinase for further development of potent drugs to treat colorectal cancer.
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TL;DR: In this article, the OPLS-AA force field and radial distribution function (RDF) were employed to calculate absolute binding constants of pyridine molecules to amino group (NH 2 ) and amide group hydrogen atoms in and first generation poly(amidoamine) dendrimers in chloroform.
Abstract: OPLS-AA force field and direct integration of intermolecular radial distribution functions (RDF) were employed to calculate absolute binding constants of pyridine molecules to amino group (NH 2 ) and amide group hydrogen atoms in and first generation poly(amidoamine) dendrimers in chloroform. The average errors in the absolute and relative association constants, as predicted with the calculations, are 14.1% and 10.8%, respectively, which translate into ca. 0.08 and 0.06 kcal/mol errors in the absolute and relative binding free energies. We believe that this level of accuracy proves the applicability of the OPLS-AA, force field, in combination with the direct RDF integration, to reproducing and predicting absolute intermolecular association constants of low magnitudes (ca. 0.2-2.0 range).
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TL;DR: Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand to find the best docked pose using a model energy function that combines empirical and force-field-based terms.
Abstract: Unlike other methods for docking ligands to the rigid 3D structure of a known protein receptor, Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand In this search, an initial rough positioning and scoring phase that dramatically narrows the search space is followed by torsionally flexible energy optimization on an OPLS-AA nonbonded potential grid for a few hundred surviving candidate poses The very best candidates are further refined via a Monte Carlo sampling of pose conformation; in some cases, this is crucial to obtaining an accurate docked pose Selection of the best docked pose uses a model energy function that combines empirical and force-field-based terms Docking accuracy is assessed by redocking ligands from 282 cocrystallized PDB complexes starting from conformationally optimized ligand geometries that bear no memory of the correctly docked pose Errors in geometry for the top-ranked pose are less than 1 A in nearly ha
6,828 citations
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TL;DR: A range of new simulation algorithms and features developed during the past 4 years are presented, leading up to the GROMACS 4.5 software package, which provides extremely high performance and cost efficiency for high-throughput as well as massively parallel simulations.
Abstract: Motivation: Molecular simulation has historically been a low-throughput technique, but faster computers and increasing amounts of genomic and structural data are changing this by enabling large-scale automated simulation of, for instance, many conformers or mutants of biomolecules with or without a range of ligands. At the same time, advances in performance and scaling now make it possible to model complex biomolecular interaction and function in a manner directly testable by experiment. These applications share a need for fast and efficient software that can be deployed on massive scale in clusters, web servers, distributed computing or cloud resources.
Results: Here, we present a range of new simulation algorithms and features developed during the past 4 years, leading up to the GROMACS 4.5 software package. The software now automatically handles wide classes of biomolecules, such as proteins, nucleic acids and lipids, and comes with all commonly used force fields for these molecules built-in. GROMACS supports several implicit solvent models, as well as new free-energy algorithms, and the software now uses multithreading for efficient parallelization even on low-end systems, including windows-based workstations. Together with hand-tuned assembly kernels and state-of-the-art parallelization, this provides extremely high performance and cost efficiency for high-throughput as well as massively parallel simulations.
Availability: GROMACS is an open source and free software available from http://www.gromacs.org.
Contact: erik.lindahl@scilifelab.se
Supplementary information:Supplementary data are available at Bioinformatics online.
6,029 citations
TL;DR: Comparisons to results for the thymidine kinase and estrogen receptors published by Rognan and co-workers show that Glide 2.5 performs better than GOLD 1.1, FlexX 1.8, or DOCK 4.01.
Abstract: Glide's ability to identify active compounds in a database screen is characterized by applying Glide to a diverse set of nine protein receptors. In many cases, two, or even three, protein sites are employed to probe the sensitivity of the results to the site geometry. To make the database screens as realistic as possible, the screens use sets of “druglike” decoy ligands that have been selected to be representative of what we believe is likely to be found in the compound collection of a pharmaceutical or biotechnology company. Results are presented for releases 1.8, 2.0, and 2.5 of Glide. The comparisons show that average measures for both “early” and “global” enrichment for Glide 2.5 are 3 times higher than for Glide 1.8 and more than 2 times higher than for Glide 2.0 because of better results for the least well-handled screens. This improvement in enrichment stems largely from the better balance of the more widely parametrized GlideScore 2.5 function and the inclusion of terms that penalize ligand−protei...
4,801 citations
3,164 citations
TL;DR: Compound 13 was orally active in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete tumor regressions and low toxicity at multiple dose levels.
Abstract: A series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole-5-carboxamides was identified as potent Src/Abl kinase inhibitors with excellent antiproliferative activity against hematological and solid tumor cell lines. Compound 13 was orally active in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete tumor regressions and low toxicity at multiple dose levels. On the basis of its robust in vivo activity and favorable pharmacokinetic profile, 13 was selected for additional characterization for oncology indications.
1,272 citations