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

Area of Science:

• Biochemistry and Molecular Biology
• Drug Discovery and Medicinal Chemistry

Background:

• Post-translational modification of microtubules is implicated in various diseases, including cancer.
• Alpha Tubulin Acetyltransferase 1 (ATAT1) is a key enzyme for alpha-tubulin acetylation at Lys-40, a significant drug target lacking inhibitors.

Purpose of the Study:

• To develop statistically constructed pharmacophore anchor models for ATAT1 to guide drug design and elucidate binding mechanisms.
• To identify compound moiety preferences and physico-chemical properties crucial for ATAT1 binding site interaction.

Main Methods:

• Statistical construction of pharmacophore anchor models using thousands of docked compounds.
• Analysis of conserved moieties interacting with identified sub-pockets (S1 acetyl, S2 adenine, S3 diphosphate sites).
• Validation through analysis of homologous protein sequences and structures with bound ligands and mutations.

Main Results:

• The models revealed three primary sub-pockets within the ATAT1 binding site: S1 (acetyl), S2 (adenine), and S3 (diphosphate).
• Key anchors were identified, showing conserved moiety interactions with sub-pocket residues, crucial for guiding inhibitor discovery.
• Virtual screening using the developed models successfully predicted several potential ATAT1 inhibitors.

Conclusions:

• The developed pharmacophore anchor models provide valuable insights into ATAT1 binding mechanisms and compound interactions.
• These models are instrumental for future inhibitor discovery and optimizing lead compounds targeting ATAT1.
• The study offers a robust framework for advancing drug development against ATAT1-related diseases.