Comparison of ATP-binding pockets and discovery of homologous recombination inhibitors

Vincent Blay, Saule Gailiunaite, Chih-Ying Lee, Hao-Yen Chang, Ted Hupp, Douglas R. Houston, Peter Chi

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

The ATP binding sites of many enzymes are structurally related, which complicates their development as therapeutic targets. In this work, we explore a diverse set of ATPases and compare their ATP binding pockets using different strategies, including direct and indirect structural methods, in search of pockets attractive for drug discovery. We pursue different direct and indirect structural strategies, as well as ligand ability assessments to help guide target selection. The analyses indicate human RAD51, an enzyme crucial in homologous recombi-nation, as a promising, tractable target. Inhibition of RAD51 has shown promise in the treatment of certain cancers but more potent inhibitors are needed. Thus, we design compounds computationally against the ATP binding pocket of RAD51 with consideration of multiple criteria, including predicted specificity, drug-likeness, and toxicity. The molecules designed are evaluated experimentally using molecular and cell-based assays. Our results provide two novel hit compounds against RAD51 and illustrate a computational pipeline to design new inhibitors against ATPases.
Original languageEnglish
Article number116923
Number of pages10
JournalBioorganic and Medicinal Chemistry
Early online date9 Jul 2022
Publication statusPublished - 15 Sept 2022

Keywords / Materials (for Non-textual outputs)

  • virtual screening
  • cheminformatics
  • drug design
  • docking
  • binding pocket
  • ligandability
  • recombinase
  • RAD51
  • ATP


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