Quercetin and Its Structural Analogs as NUDT5 Inhibitors: A Preliminary In Silico Study

Nucleotide diphosphate hydrolase type 5 (NUDT5) plays a significant role in the estrogen-signaling pathway and is overexpressed in breast cancer. This study aimed to explore the anti-breast cancer potential of quercetin and its 52 structural analogs by targeting the NUDT5 enzyme using the in silico molecular docking method. Moreover, Molecular Mechanics/General Born Surface Area (MM/GBSA) calculations were performed for compounds with superior binding affinity scores than quercetin. Their drug-likeness, according to Lipinski’s rule of five, water solubility, and Caco-2 permeability were predicted. In addition, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile was determined for the top-scoring compounds from the docking studies and MM/GBSA calculations, as well as for those that complied with the rules of Lipinski and exhibited high permeability. The obtained results showed that all the tested ligands interact with the active site of NUDT5. Their binding energies ranged from −11.24 to −7.36 kcal/mol. The MM/GBSA calculations further supported the binding affinity predictions. ADMET analysis enabled the selection of compounds with favorable pharmacokinetic profiles in comparison to quercetin. Quercetin analogs L1 and L28 were identified as promising anti-breast cancer drug candidates worthy of further experimental evaluation.