Integrated experimental and computational study of a novel indenonaphthodiazepine[5.3.3]propellane as a potential inhibitor of Mcl-1
- 1Department of Chemistry, Faculty of Science, Imam Khomeini International University Qazvin Iran
- 2Department of Chemistry, Faculty of Science, University of Guilan Rasht Iran
Abstract
Myeloid cell leukemia-1 (Mcl-1) is a key anti-apoptotic protein that drives resistance to chemotherapy, making it a critical oncology target. In this study, we synthesized a new indenonaphthodiazepine[5.3.3]propellane via a one-pot multicomponent reaction and characterized its structure by FT-IR, 1H-NMR, 13C-NMR, and mass spectrometry. Density functional theory (DFT) calculations at the B3LYP/6-31G (d) level were carried out to study its electronic features and reactive centers. In molecular docking against Mcl-1, the propellane derivative showed a binding score of −5.678 kcal mol−1, outperforming the reference inhibitor AMG-176 (−3.428 kcal mol−1). Subsequent 200 ns molecular dynamics (MD) simulations confirmed that the ligand remained stable in the binding pocket, maintaining lower root-mean-square deviation (RMSD) and root mean square fluctuation (RMSF) values than AMG-176 through key hydrophobic, π–alkyl, and π–sulfur contacts. Furthermore, in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) evaluation indicated full compliance with Lipinski's and Veber's criteria, high human intestinal absorption (>95%), and no predicted hERG or liver toxicity. Crucially, while AMG-176 was predicted to inhibit CYP3A4, the propellane showed no CYP3A4 inhibition, suggesting a lower potential for drug–drug interactions. These data demonstrate that this propellane framework serves as a promising starting point for Mcl-1 targeted drug discovery.
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BibTeX
@article{bijarbone2026integrated,
title = {{Integrated experimental and computational study of a novel indenonaphthodiazepine[5.3.3]propellane as a potential inhibitor of Mcl-1}},
author = {Sahar Bagheri Bijarbone and Mohammad Bayat and Davood Gheidari},
journal = {Nanoscale advances},
year = {2026},
month = nov,
doi = {10.1039/d6na00844e},
url = {https://europepmc.org/article/PMC/PMC13725704},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Integrated experimental and computational study of a novel indenonaphthodiazepine[5.3.3]propellane as a potential inhibitor of Mcl-1
AU - Sahar Bagheri Bijarbone
AU - Mohammad Bayat
AU - Davood Gheidari
PY - 2026
DA - 2026/11/02
JO - Nanoscale advances
DO - 10.1039/d6na00844e
UR - https://europepmc.org/article/PMC/PMC13725704
AB - Myeloid cell leukemia-1 (Mcl-1) is a key anti-apoptotic protein that drives resistance to chemotherapy, making it a critical oncology target. In this study, we synthesized a new indenonaphthodiazepine[5.3.3]propellane via a one-pot multicomponent reaction and characterized its structure by FT-IR, 1H-NMR, 13C-NMR, and mass spectrometry. Density functional theory (DFT) calculations at the B3LYP/6-31G (d) level were carried out to study its electronic features and reactive centers. In molecular docking against Mcl-1, the propellane derivative showed a binding score of −5.678 kcal mol−1, outperforming the reference inhibitor AMG-176 (−3.428 kcal mol−1). Subsequent 200 ns molecular dynamics (MD) simulations confirmed that the ligand remained stable in the binding pocket, maintaining lower root-mean-square deviation (RMSD) and root mean square fluctuation (RMSF) values than AMG-176 through key hydrophobic, π–alkyl, and π–sulfur contacts. Furthermore, in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) evaluation indicated full compliance with Lipinski's and Veber's criteria, high human intestinal absorption (>95%), and no predicted hERG or liver toxicity. Crucially, while AMG-176 was predicted to inhibit CYP3A4, the propellane showed no CYP3A4 inhibition, suggesting a lower potential for drug–drug interactions. These data demonstrate that this propellane framework serves as a promising starting point for Mcl-1 targeted drug discovery.
SN - 2516-0230
ER -