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Published on: September 20, 2016
Quercetin and Its Structural Analogs as NUDT5 Inhibitors: A Preliminary In Silico Study
Emilia Gligorić1, Milica Vidić1, Branislava Teofilović1
1Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia.
Abstract:
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.
Insights
Quercetin analogs show promise as anti-breast cancer agents by inhibiting the NUDT5 enzyme. Computational analysis identified specific compounds with favorable drug-like properties for further research.
Area of Science:
- Biochemistry
- Computational Chemistry
- Oncology
Background:
- Nucleotide diphosphate hydrolase type 5 (NUDT5) is implicated in estrogen signaling and overexpressed in breast cancer.
- Targeting NUDT5 presents a potential therapeutic strategy for breast cancer treatment.
Purpose of the Study:
- To evaluate the in silico anti-breast cancer potential of quercetin and its analogs against the NUDT5 enzyme.
- To identify promising drug candidates with favorable pharmacokinetic properties.
Main Methods:
- In silico molecular docking simulations were employed to assess binding affinities.
- Molecular Mechanics/General Born Surface Area (MM/GBSA) calculations refined affinity predictions.
- Drug-likeness (Lipinski's rule of five), solubility, Caco-2 permeability, and ADMET profiles were predicted.
Main Results:
- All tested compounds interacted with the NUDT5 active site, with binding energies ranging from -11.24 to -7.36 kcal/mol.
- MM/GBSA calculations corroborated docking results.
- ADMET profiling identified quercetin analogs L1 and L28 with favorable pharmacokinetic profiles and high permeability.
Conclusions:
- Quercetin analogs L1 and L28 demonstrate significant potential as anti-breast cancer drug candidates.
- These compounds warrant further experimental validation for their therapeutic efficacy against NUDT5.
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