Introducing New Inhibitors of PAICS, a De Novo Purine Biosynthesis Enzyme, through Structure-Based Virtual Screening.

Background: Cancer cells need many purine nucleotides during their uncontrolled proliferation. phosphoribosyl-aminoimidazole carboxylase and phosphoribosylaminoimidazole-succinocarboxamide synthetase (PAICS) is one of the enzymes involved in de novo purine biosynthesis. The PAICS gene is overexpressed in some types of cancer, and PAICS knockdown results in tumor growth reduction in vitro and in vivo. Therefore, targeting PAICS enzyme activity can be a promising approach for cancer treatment.

Objective: The present study aimed to identify the inhibitors of PAICS using in silico drug screening strategies.

Materials and methods: The crystal structure of PAICS (PDB ID: 7ALE) was downloaded and prepared by the UCSF Chimera software. 7ALE is in a complex with a ligand called RLK. Swiss Similarity and PubChem were searched for molecules similar to RLK. A library of 375 molecules was found and docked to PAICS using PyRx 0.8. Six complexes with energy rates more negative than 10 and RMSD of 0 were analyzed by Biovia Discovery Studio to find interacting residues. The Pharmacokinetic properties of these ligands were predicted by ADMETlab 2.0.

Results: The findings showed that the best six ligands are the derivatives of carboxamide, acetamide, propanamide, urea, carboxamide, and pentanediamide, respectively. They bind to the SACAIRs' active site of PAICS. Regarding their predicted toxicity and pharmacokinetic properties, molecules #2 and #4 were more acceptable than the others.

Conclusion: In this study, six potential inhibitors of PAICS were predicted through virtual screening. Evaluating the efficacy of these inhibitors for treating different types of cancers, especially leukemia, is recommended. This may be a starting point for the development of new PAICS inhibitors..