The iterative application of a large chemical space in the drug discovery process




chemical space, 1,2,4-triazole, tetrazole, BRD4, thermal shift assay


Aim. To demonstrate the advantages of large-scale virtual libraries generated using chemical protocols previously validated in primary steps of the drug discovery process.
Results and discussion. Two validated parallel chemistry protocols reported earlier were used to create the chemical space. It was then sampled based on diversity metric, and the sample was subjected to the virtual screening on BRD4 target. Hits of virtual screening were synthesized and tested in the thermal shift assay.
Experimental part. The chemical space was generated using commercially available building blocks and synthetic protocols suitable for parallel chemistry and previously reported. After narrowing it down, using MedChem filters, the resulting sub-space was clustered based on diversity metrics. Centroids of the clusters were put to the virtual screening against the BRD4 active center. 29 Hits from the docking were synthesized and subjected to the thermal shift assay with BRD4, and 2 compounds showed noticeable dTm.
Conclusions. A combination of cheminformatics and molecular docking was applied to find novel potential binders for BRD4 from a large chemical space. The selected set of predicted molecules was synthesized with a 72 % success rate and tested in a thermal shift assay to reveal a 6 % hit rate. The selection can be performed iteratively to fast support of the drug discovery.

Supporting Agency

  • The work was funded by Enamine Ltd and NIH (grant No. GM133836 to Prof. John J. Irwin and Y.S.M.)


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How to Cite

Savych, O. V.; Gryniukova, A. V.; Alieksieieva, D. O.; Dziuba, I. M.; Borysko, P. O.; Dudenko, D. V.; Brovarets, V. S.; Moroz, Y. S. The Iterative Application of a Large Chemical Space in the Drug Discovery Process. J. Org. Pharm. Chem. 2022, 19, 3-11.



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