In silico screening of DEAB analogues as ALDH1 isoenzymes inhibitors in cancer treatment

Inhibiting aldehyde dehydrogenase (ALDH) isoenzymes show promise in cancer treatment, especially as various cancer types exhibit elevated activities of ALDH1 isoenzymes. Several inhibitory drugs, including diethylaminobenzaldehyde (DEAB), have been studied, and demonstrate high efficacy in combating tumor proliferation and enhancing chemotherapy. Even then, significant drawbacks such as low solubility, cytotoxicity, and inconsistent potency have resulted in DEAB’s poor efficacy as cancer therapeutics. In this study, we performed in silico screening tests to analyze 55 DEAB analogs – classified into three different scaffolds – to identify new compounds with enhanced ligand binding affinity and reduced toxicity. Given that the ALDH1 active site is predominantly composed of nonpolar residues, we hypothesized that analogs that have low polarity would have lower (better) free energies of binding. Through molecular docking, we found that analogs that are highly hydrophobic with more aromatic rings, higher molecular weights, and high molar refractivity (indicating high polarizability) had significantly stronger binding affinities. Among the analogs screened, analogs 16 and 17 had the best docking scores among ligands that met the drug-like criteria for bioavailability. They had high logPs, indicating high hydrophobicity. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) test also deemed both ligands non-toxic toward human cell culture. However, other analogs with lower logP exhibited high (worse) docking scores among ligands that met the drug-like criteria for bioavailability. With these results highlighting promising ALDH1 isoenzyme inhibitors, a proper in vitro procedure testing ligands 16 and 17 is essential to validate the inhibitory efficacy and cytotoxicity of these two potential therapeutics.