Quantum DFT analysis and molecular docking investigation of various potential breast cancer drugs
Md Ashraf Ayub1, Ankit Raj Tyagi1, Sunil Kumar Srivastava2
1Department of Zoology, School of Life Sciences, Mahatma Gandhi Central University, Motihari-845401, Bihar, India. pranveersingh@mgcub.ac.in.
Abstract:
Breast cancer is among the deadliest cancers worldwide, highlighting the urgent need for effective treatments. This study employs density functional theory (DFT) and molecular docking analyses to evaluate the anti-cancer efficacy and specificity of drug molecules lapatinib, tucatinib, neratinib, anastrozole, and letrozole. DFT analysis provides comprehensive insights into the structural, electronic, optical, and vibrational properties of these drugs, helping to elucidate their molecular stability and reactivity through global reactivity descriptors. Additionally, molecular docking simulations reveal the binding conformations and interaction profiles of these drugs with key breast cancer targets, underscoring their therapeutic potential. Docking results indicate that lapatinib, tucatinib, and neratinib have high binding affinities for HER2, with lapatinib exhibiting the strongest overall binding, particularly with PDK1 (PDB ID: 1UU7), PAK4 (PDB ID: 2X4Z), GSK3 (PDB ID: 1GNG), and HER2 (PDB ID: 2IOK). The stable hydrogen bonding and other interactions observed with lapatinib support its effectiveness in treating HER2-positive breast cancers, tucatinib's selective HER2 binding reduces off-target effects, while neratinib's irreversible binding provides prolonged inhibition, making it useful for overcoming resistance in HER2-positive cases. In contrast, anastrozole and letrozole show lower binding affinities for HER2 and EGFR due to their simpler structures but are potent aromatase inhibitors, making them effective in treating estrogen receptor-positive (ER-positive) breast cancers. In conclusion, DFT and molecular docking studies affirm the suitability of lapatinib, tucatinib, and neratinib for HER2-positive cancers, while anastrozole and letrozole are effective in ER-positive cancers, emphasizing the role of molecular structure and binding affinity in optimizing cancer treatment strategies.
Insights
This study used computational methods to assess anti-cancer drugs. Lapatinib, tucatinib, and neratinib are effective for HER2-positive breast cancer, while anastrozole and letrozole target ER-positive breast cancer.
Area of Science:
- Computational chemistry
- Molecular modeling
- Drug discovery
Background:
- Breast cancer remains a leading cause of cancer mortality globally, necessitating novel therapeutic strategies.
- Targeted therapies are crucial for improving patient outcomes in breast cancer treatment.
- Understanding drug-target interactions at a molecular level is key to optimizing efficacy.
Purpose of the Study:
- To evaluate the anti-cancer efficacy and specificity of lapatinib, tucatinib, neratinib, anastrozole, and letrozole using computational methods.
- To elucidate the molecular properties and binding interactions of these drugs with breast cancer targets.
- To correlate molecular characteristics with therapeutic potential in different breast cancer subtypes.
Main Methods:
- Density Functional Theory (DFT) analysis was performed to investigate the structural, electronic, optical, and vibrational properties of the drug molecules.
- Global reactivity descriptors were calculated to assess molecular stability and reactivity.
- Molecular docking simulations were employed to predict binding conformations and affinities with key breast cancer targets (e.g., HER2, EGFR, aromatase).
Main Results:
- DFT analysis provided insights into the inherent properties of the drug molecules.
- Molecular docking revealed high binding affinities for lapatinib, tucatinib, and neratinib with HER2, with lapatinib showing strong interactions with multiple targets.
- Anastrozole and letrozole demonstrated lower binding affinities for HER2/EGFR but are potent aromatase inhibitors, indicating efficacy in ER-positive breast cancer.
Conclusions:
- Computational studies confirm lapatinib, tucatinib, and neratinib as promising agents for HER2-positive breast cancers.
- Anastrozole and letrozole are effective for ER-positive breast cancers due to their aromatase inhibition.
- Molecular structure and binding affinity are critical determinants for optimizing breast cancer treatment strategies.
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