Pharmacophore anchor models of ATAT1 to discover potential inhibitors and lead optimization. (August 2021)

• Record Type: Journal Article
• Authors: Hsu, Nung-Yu; Pathak, Nikhil; Chen, Yun-Ti; Hsu, Yen-Chao; Yang, Jinn-Moon
• Is Part Of: Computational biology and chemistry. Volume 93(2021)
• Publication Date: 2021-08
• Subjects: ATAT1 inhibitor -- Pharmacophore anchor model -- Virtual screening; Chemistry -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; Biochemistry -- Data processing; Biology -- Data processing; Molecular biology -- Data processing; Periodicals; Electronic journals; 542.85
• DOI: 10.1016/j.compbiolchem.2021.107513
• Languages: English
• ISSNs: 1476-9271

Abstract

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.