The manuscript entitled “Transcription Factor DLX5 As a New Target for Promising Antitumor Agents” by the Quantum Team
The reference:
Transcription factor DLX5 is a new target for promising antitumor agents.
The High Throughput Screening
The overexpression of the DLX5 gene in mammalian cells stimulates cell proliferation and can be observed in endome-trial carcinoma, non-small cell lung cancer (nScLc), and small cell lung cancer. The knockdown of the DLX5 expression using sirnA in mouse and human cancer cells results in the arrest of cell proliferation.
New data point to the fact that DLX5 has a direct effect on the expression of protooncogene c-myc. These facts allow us to regard DLX5 as a promising target for which specific ligands that have the properties of oncogenesis inhibitors can be found.
Attempts have frequently been made to use the so-called “high throughput screening” to solve the problem of the search for the ligands of a certain protein. This screening is carried out on a cell culture or on an in vitro model, using an earlier prepared compound library.
The logistics and cost of the studies required for the experimental validation of a significant number of molecules is prohibitively high in many cases. On account of these reasons, in the present study we used the algorithm earlier elaborated to search for inhibitors of new protein targets, based on the analysis of the crystal structure of a target protein. the algorithm is based on the molecular docking of chemical compounds to the known 3D model of a target protein, which predicts the possible position of a compound in the protein–ligand binding site, the calculation of the molecular dynamics being used to refine the binding energies for the best suiting compounds.
Ligand preparation and molecular docking
In order to optimize the time of computational screening, the ENAMINE library consisting of 106 compounds was clustered using the Jarvis–Patrick algorithm with acceleration, which is contained in the QUANTUM software package. The so-called tanimoto metric was calculated using the Daylight molecular fingerprints, which were selected as the measure of molecular similarity. The parameters of clusterization were selected in such a manner that each cluster consisted, on average, of approximately 10 related structures; the total number of non-clustered molecules being no higher than 20% of the initial amount of the library compounds. the compounds representing the centroids of clusters were then selected for further screening. In order to enhance the speed of molecular docking, from the entire centroid library were selected the molecules with the low molecular weight.
All the selected compounds were extracted from the sdf files provided by ENAMINE and processed in the batch-mode. The library had not been additionally enriched with molecules active towards oncotargets or by any other methods. the typization of protein and ligands, as well as in silico screening, was carried out using the corresponding tools from the QUANTUM software package.
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