Pharmacophore anchor models of ATAT1 to discover potential inhibitors and lead optimization

Nung Yu Hsu, Nikhil Pathak, Yun Ti Chen, Yen Chao Hsu, Jinn-Moon Yang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Post-translation modification of microtubules is associated with many diseases like cancer. Alpha Tubulin Acetyltransferase 1 (ATAT1) is a major enzyme that acetylates ‘Lys-40’ in alpha-tubulin on the luminal side of microtubules and is a drug target that lacks inhibitors. Here, we developed pharmacophore anchor models of ATAT1 which were constructed statistically using thousands of docked compounds, for drug design and investigating binding mechanisms. Our models infer the compound moiety preferences with the physico-chemical properties for the ATAT1 binding site. The results from the pharmacophore anchor models show the three main sub-pockets, including S1 acetyl site, S2 adenine site, and S3 diphosphate site with anchors, where conserved moieties interact with respective sub-pocket residues in each site and help in guiding inhibitor discovery. We validated these key anchors by analyzing 162 homologous protein sequences (>99 species) and over 10 structures with various bound ligands and mutations. Our results were consistent with previous works also providing new interesting insights. Our models applied in virtual screening predicted several ATAT1 potential inhibitors. We believe that our model is useful for future inhibitor discovery and for guiding lead optimization.

Original languageEnglish
Article number107513
Pages (from-to)1-8
Number of pages8
JournalComputational Biology and Chemistry
Volume93
DOIs
StatePublished - Aug 2021

Keywords

  • ATAT1 inhibitor
  • Pharmacophore anchor model
  • Virtual screening

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